This application is the National Phase filing of International Patent Application No. PCT/JP00/04034, filed Jun. 21, 2000.
The present invention relates to novel acyl hydrazine derivatives which inhibit activated coagulation factor X (FXa) to exhibit anti-coagulative effect and which are useful as pharmaceuticals, as well as their production and use.
It is important to inhibit the formation of a thrombus in preventing and treating cardiac infarction, cerebral thrombosis and the like, and various anti-thombotic agents such as anti-thrombin agents and platelet aggregation inhibitors have been developed. Nevertheless, platelet aggregation inhibitors as well as anti-thrombin agents have bleeding side effects and problems in their safety, since these agents posses a platelet aggregation-inhibiting activity in combination with anticoagulative effect. On the other hand, FXa inhibitors specifically inhibit on a coagulation factor, and thus are useful as anticoagulant.
So far, compounds having FXa-inhibiting effects are disclosed for example in JP-A-7-112970, JP-A-5-208946, WO-96/16940, WO96/40679 and WO 96/10022, as well as Journal of Medicinal Chemistry, Vol.41, page 3357 (1998), etc.
Since such compounds having FXa-inhibiting effects described above do not have sufficient FXa-inhibiting effects and, in particular, do not exhibit sufficient activities when given orally, therefore, they have not been successful in giving any practically satisfactory pharmaceutical effects.
The invention provides novel acylhydrazine derivatives which specifically inhibit FXa, which are capable of being given orally and which are useful as a pharmaceutical capable of being used safely in preventing and treating a disease associated with thrombus or infarction.
The present inventors made an effort and finally was successful for the first time to synthesis a compound characterized chemically by the presence of a two nitrogen atoms [nitrogen atom in xe2x80x94n(R2)xe2x80x94; and nitrogen atom in xe2x80x94n(R3)xe2x80x94 or xe2x80x94Nxe2x95x90] adjacent to a carbonyl group and the presence of an optionally substituted amino group, an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group at its terminal, i.e., a compound represented by Formula: 
wherein R is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, each of R1 and R2 is a hydrogen atom or an optionally substituted hydrocarbon group, or R1 and R2 or a substituent on X1 and R2 are bound to each other to form an optionally substituted ring, each of X1 and X2 is a bond, an optionally substituted alkylene group or an optionally substituted imino group, D is an oxygen atom or a sulfur atom, A is xe2x80x94N(R3)xe2x80x94Yxe2x80x94 or xe2x80x94Nxe2x95x90Yxe2x80x94, R3 is a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group, Y is an optionally substituted linear hydrocarbon group or an optionally substituted cyclic group, Z is (1) an optionally substituted amino group, (2) an optionally substituted imidoyl group or (3) an optionally substituted nitrogen-containing heterocyclic group or a salt thereof (hereinafter sometimes referred to as Compound (I)), and discovered that this compound exhibits an unexpectedly excellent FXa inhibiting effect due to its particular chemical structure, and thus can safely be given orally as a prophylactic and therapeutic agent for a disease associated with a thrombus or an infarction, thus establishing the invention.
Accordingly, the invention relates to:
(1) a Compound (I);
(2) a prodrug of a compound according to Section (1) described above or a salt thereof;
(3) a compound according to Section (1) described above wherein R is an optionally substituted hydrocarbon group;
(4) a compound according to Section (1) described above wherein R is an optionally substituted heterocyclic group;
(5) a compound according to Section (1) described above wherein R is a halogen atom or an aryl group optionally substituted by a C2-4 alkenyl;
(6) a compound according to Section (1) described above wherein R is a naphthyl group optionally substituted by a halogen atom;
(7) a compound according to Section (1) described above wherein R is a benzopyranyl group optionally substituted by a halogen atom;
(8) a compound according to Section (1) described above wherein R1 and R2 are bound to each other and taken together with xe2x80x94Nxe2x80x94X1xe2x80x94CDxe2x80x94Nxe2x80x94 to form a group represented by Formula: 
wherein X3 is an optionally substituted C1-2 alkylene, X4 is an optionally substituted C1-3 alkylene and D is an oxygen atom or a sulfur atom;
(9) a compound according to Section (1) described above wherein R1 and R2 are bound to each other and taken together with xe2x80x94Nxe2x80x94X1xe2x80x94CDxe2x80x94Nxe2x80x94 to form a group represented by Formula: 
wherein n is 1 or 2, mxe2x80x3 is 1 or 2, R8 is a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted mercapto group, a nitro group, a cyano group, an optionally substituted amino group, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group or an optionally substituted sulfamoyl group (preferably, a hydrogen atom, an optionally substituted lower alkyl group, a cyano group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group or an optionally substituted thiocarbamoyl group), and D is an oxygen atom or a sulfur atom;
(10) a compound according to Section (1) described above wherein R1 and R2 are bound to each other and taken together with xe2x80x94Nxe2x80x94X1xe2x80x94CDxe2x80x94Nxe2x80x94 to form a group represented by Formula: 
wherein n is 1 or 2 and m is 2 or 3.
(11) a compound according to Section (10) described above wherein n=1 and m=2;
(12) a compound according to Section (1) described above wherein a substituent on X1 and R2 are bound to each other and a divalent group represented by xe2x80x94X1xe2x80x94CDxe2x80x94N(R2)xe2x80x94 is a group represented by Formula: 
wherein X5 is a bond or an optionally substituted methylene, X6 is an optionally substituted C2-3 alkylene and D is an oxygen atom or a sulfur atom;
(13) a compound according to Section (1) described above wherein a substituent on X1 and R2 are bound to each other and a divalent group represented by xe2x80x94X1xe2x80x94CDxe2x80x94N(R2)xe2x80x94 is a group represented by Formula: 
wherein nxe2x80x2 is 0 or 1 and mxe2x80x2 is 2 or 3;
(14) a compound according to Section (13) described above wherein nxe2x80x2=0 and mxe2x80x2=2;
(15) a compound according to Section (1) described above wherein each of R1 and R2 is a hydrogen atom or an optionally substituted lower alkyl;
(16) a compound according to Section (1) described above wherein an optionally substituted imino group is a group represented by Formula xe2x80x94N(R4)xe2x80x94 wherein R4 is a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group;
(17) a compound according to Section (1) described above wherein X1 is methylene;
(18) a compound according to Section (1) described above wherein X2 is a bond;
(19) a compound according to Section (1) described above wherein R3 is a hydrogen atom, an optionally substituted lower alkyl group, formyl or an optionally substituted lower alkanoyl group;
(20) a compound according to Section (1) described above wherein R3 is a hydrogen atom or an optionally substituted lower alkyl group;
(21) a compound according to Section (1) described above wherein Y is an optionally substituted cyclic hydrocarbon group;
(22) a compound according to Section (1) described above wherein A is xe2x80x94N(R3)xe2x80x94Yxe2x80x94 and Y is an optionally substituted phenylene;
(23) a compound according to Section (1) described above wherein Y is an optionally substituted heterocyclic group;
(24) a compound according to Section (1) described above wherein Y is an optionally substituted piperidine residue;
(25) a compound according to Section (1) described above wherein Z is an optionally substituted nitrogen-containing heterocyclic group;
(26) a compound according to Section (1) described above wherein D is an oxygen atom;
(27) a compound selected from the group consisting of 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-[1-(4-pyridyl)piperidin-4-ylamino]-2-piperazinone, 4-(6-chloronaphthalene-2-sulfonyl)-1-[1-(4-pyridyl)piperidin-4-ylamino]-2-piperazinone, 4-(6-bromonaphthalene-2-sulfonyl)-1-[1-(4-pyridyl)piperidin-4-ylamino]-2-piperazinone, 4-(7-bromo-2H-benzopyran-3-sulfonyl)-1-[1-(4-pyridyl)piperidin-4-yl]amino}-2-piperazinone, 4-(6-chloronaphthalene-2-sulfonyl)-1-{methyl[1-(4-pyridyl)piperidin-4-yl]amino}-2-piperazinone, 4-(6-bromonaphthalene-2-sulfonyl)-1-{methyl[1-(4-pyridyl)piperidin-4-yl]amino}-2-piperazinone, 4-(7-bromo-2H-benzopyran-3-sulfonyl)-1-{methyl[1-(4-pyridyl)piperidin-4-yl]amino}-2-piperazinone, 4-(6-chloronaphthalene-2-sulfonyl)-1-{methyl[1-(4-pyridyl)piperidin-4-yl]amino}-2-piperazinone, 4-(6-chloronaphthalene-2-sulfonyl)-1-{methyl[1-(2-methyl-4-pyridyl)piperidin-4-yl]amino}-2-piperazinone, {[4-(6-chloronaphthalene-2-sulfonyl)-2-oxo-1-piperazinyl][1-(2-methyl-4-pyridyl)-4-piperidinyl]amino}acetic acid, 4-(6-chloronaphthalene-2-sulfonyl)-1-{[1-(4-pyridyl)-4-piperidinyl]amino}-6-oxo-2-piperazinecarboxylic acid, 4-(6-chloronaphthalene-2-sulfonyl)-1-{methyl[1-(4-pyridyl)-4-piperidinyl]amino}-6-oxo-2-piperazinecarboxylic acid, 4-(6-chloronaphthalene-2-sulfonyl)-1-{methyl[1-(4-pyridyl)-4-piperidinyl]amino}-6-oxo-2-piperazinecarboxamide, 4-(6-chloronaphthalene-2-sulfonyl)-1-{methyl[1-(2-methyl-4-pyridyl)-4-piperidinyl]amino}-6-oxo-2-piperazinecarboxamide, 4-(6-chloronaphthalene-2-sulfonyl)-6-hydroxymethyl-1-{methyl[1-(4-pyridyl)-4-piperidinyl]amino}-2-piperazinone, 6-aminomethyl-4-(6-chloronaphthalene-2-sulfonyl)-1-{methyl[1-(4-pyridyl)-4-piperidinyl]amino}-2-piperazinone, 6-acetylaminomethyl-4-(6-chloronaphthalene-2-sulfonyl)-1-{methyl[1-(4-pyridyl)-4-piperidinyl]amino}-2-piperazinone, 4-(6-chloronaphthalene-2-sulfonyl)-1-{[1-(4-pyridyl)-4-piperidinyl]amino}-6-oxo-2-piperazineacetic acid and 4-(6-chloronaphthalene-2-sulfonyl)-1-{[1-(2-methyl-4-pyridyl)-4-piperidinyl]amino}-6-oxo-2-piperazineacetic acid as well as a salt thereof;
(28) a prodrug of a compound according to Section (27) described above or a salt thereof;
(29) a pharmaceutical composition comprising a compound according to Section (1) described above or a salt thereof;
(30) a composition according to Section (29) described above which is an anticoagulant;
(31) a composition according to Section (29) described above which is an activated coagulation factor X inhibitor;
(32) a composition according to Section (29) described above which is a prophylactic and therapeutic agent for cardiac infarction, cerebral thrombosis or deep vein thrombosis;
(33) a method for producing a compound according to Section (1) described above or a salt thereof comprising:
reacting a compound represented by Formula (II) RSO2Q wherein Q is a leaving group and other symbols are defined as described in Section (1) described above or a salt thereof with a compound represented by Formula (III): 
xe2x80x83wherein the symbols are defined as described in Section (1) described above or a salt thereof; or,
reacting a compound represented by Formula (IV): 
wherein Q1 is a leaving group and other symbols are defined as described in Section (1) described above or a salt thereof with a compound represented by Formula (V): 
xe2x80x83wherein the symbols are defined as described in Section (1) described above or a salt thereof; or,
reacting a compound represented by Formnula (VI): 
wherein the symbols are defined as described in Section (1) described above or a salt thereof with a compound represented by Formula (VII):
A1xe2x80x94X2xe2x80x94Zxe2x80x83xe2x80x83(VII)
xe2x80x83wherein A1 is Q1xe2x80x94Yxe2x80x94 or Oxe2x95x90Yxe2x80x94, Q1 is a leaving group and other symbols are defined as described in Section (1) described above or a salt thereof; or, reacting a compound represented by Formula (VIII): 
wherein Q3 is a hydrogen atom or a leaving group and other symbols are defined as described in Section (1) described above or a salt thereof with a compound represented by Formula (IX):
Q4xe2x80x94Zxe2x80x83xe2x80x83(IX)
wherein Q4 is a hydrogen atom or a leaving group and other symbols are defined as described in Section (1) described above or a salt thereof;
(34) a compound represented by Formula: 
wherein each of L1a and L2a is a hydrogen atom or an amino-protecting group, R1xe2x80x2 and R2xe2x80x2 are bound to each other to form an optionally substituted ring, or R1xe2x80x2 is a hydrogen atom or an optionally substituted hydrocarbon group and a substituent of X1 and R2xe2x80x2 are bound to each other to form an optionally substituted ring, and other symbols are defined as described in Section (1) described above or a salt thereof;
(35) a compound according to Section (34) described above wherein R1xe2x80x2 and R2xe2x80x2 are bound to each other and taken together with xe2x80x94Nxe2x80x94X1xe2x80x94CDxe2x80x94Nxe2x80x94 to form a group represented by Formula: 
wherein X3 is an o ptionally substituted C1-2 alkylene, X4 is an optionally substituted C1-3 alkylene and D is an oxygen atom or a sulfur atom;
(36) a compound according to Section (34) described above 34 wherein R1 and R2 are bound to each other and taken together with xe2x80x94Nxe2x80x94X1xe2x80x94CDxe2x80x94Nxe2x80x94 to form a group represented by Formula: 
wherein n is 1 or 2, mxe2x80x3 is 1 or 2, R8 is a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted mercapto group, a nitro group, a cyano group, an optionally substituted amino group, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group or an optionally substituted sulfamoyl group (preferably, a hydrogen atom, an optionally substituted lower alkyl group, a cyano group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group or an optionally substituted thiocarbamoyl group), and D is an oxygen atom or a sulfur atom;
(37) a compound according to Section (34) described above wherein R1xe2x80x2 and R2xe2x80x2 are bound to each other and taken together with xe2x80x94Nxe2x80x94X1xe2x80x94CDxe2x80x94Nxe2x80x94 to form a group represented by Formula: 
wherein n is 1 or 2 and m is 2 or 3;
(38) a compound according to Section (37) described above wherein n=1 and m=2;
(39) a compound according to Section (34) described above wherein a substituent on X1 and R2xe2x80x2 are bound to each other and a divalent group represented by xe2x80x94X1xe2x80x94CDxe2x80x94N(R2xe2x80x2)xe2x80x94 is a group represented by Formula: 
wherein X5 is a bond or an optionally substituted methylene, X6 is an optionally substituted C2-3 alkylene and D is an oxygen atom or a sulfur atom;
(40) a compound according to Section (34) described above wherein a substituent on X1 and R2xe2x80x2 are bound to each other and a divalent group represented by xe2x80x94X1xe2x80x94CDxe2x80x94N(R2xe2x80x2)xe2x80x94 is a group represented by Formula: 
wherein nxe2x80x2 is 0 or 1 and mxe2x80x2 is 2 or 3;
(41) a compound according to Section (40) described above wherein nxe2x80x2=0 and mxe2x80x2=2;
(42) an enzyme inhibiting agent or a receptor Hmodulating agent containing a compound comprising as its moiety a divalent group represented by Formula: 
wherein R1xe2x80x2 and R2xe2x80x2 are bound to each other to form an optionally substituted ring, or R1xe2x80x2 is a hydrogen atom or an optionally substituted hydrocarbon group and a substituent of X1 and R2xe2x80x2 are bound to each other to form an optionally substituted ring, and other symbols are defined as described in Section (1) described above or a salt thereof;
(43) an agent according to Section (42) described above which is an activated coagulation factor X inhibitor;
(44) an agent according to Section (42) described above which is a prophylactic and therapeutic agent for cardiac infarction, cerebral thrombosis or deep vein thrombosis;
(45) a method for inhibiting a blood coagulation in mammals comprising administering an effective amount of a compound according to Section (1) described above or a salt thereof to said mammals;
(46) a method for inhibiting an activated coagulation factor X in mammals comprising administering an effective amount of a compound according to Section (1) Adescribed above or a salt thereof to said mammals;
(47) a method for preventing and treating cardiac infarction, cerebral thrombosis or deep vein thrombosis in mammals comprising administering an effective amount of a compound according to Section (1) described above 1 or a salt thereof to said mammals;
(48) a use of a compound according to Section (1) described above or a salt thereof for producing a pharmaceutical for inhibiting a blood coagulation;
(49) a use of a compound according to Section (1) described above or a salt thereof for producing a pharmaceutical for inhibiting an activated coagulation factor X;
(50) a use of a compound according to Section (1) described above or a salt thereof for producing a pharmaceutical for preventing and treating cardiac infarction, cerebral thrombosis or deep vein thrombosis; and the like.
In the formulae described above, R is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.
A hydrocarbon group in xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R may for example be an aliphatic linear hydrocarbon group, an alicyclic hydrocarbon group and an aryl group, with an aryl group being preferred.
xe2x80x9cAliphatic linear hydrocarbon groupxe2x80x9d as an example of a hydrocarbon group may for example be a straight or branched aliphatic hydrocarbon group such as an alkyl group, an alkenyl group and an alkynyl group.
An alkyl group mentioned here may for example be a C1-10 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl, n-heptyl, 1-methylheptyl, 1-ethylhexyl, n-octyl, 1-methylheptyl, nonyl and the like (preferably a C1-6 alkyl and the like).
An alkenyl group may for example be a C2-6 alkenyl group such as vinyl, allyl, isopropenyl, 2-methyl, allyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like.
An alkynyl group may for example be a C2-6 alkynyl group such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like.
xe2x80x9cAlicyclic hydrocarbon groupxe2x80x9d as an example of a hydrocarbon group may for example be a saturated or unsaturated alicyclic hydrocarbon group such as a cycloalkyl group, a cycloalkenyl group, a cycloalkadienyl group and the like.
xe2x80x9cCyloalkyl groupxe2x80x9d mentioned here may for example be a C3-9 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like.
xe2x80x9cCycloalkenyl groupxe2x80x9d may for example be a C3-9 cycloalkenyl group such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl, 1-cyclohexen-1-yl, 1-cyclohepten-1-yl and the like.
xe2x80x9cCycloalkadienyl groupxe2x80x9d may for example be a C4-6 cycloalkadienyl group such as 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like.
xe2x80x9cAryl groupxe2x80x9d as an example of a hydrocarbon group may for example be a monocyclic or fused polycyclic aromatic hydrocarbon group such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like, with phenyl, 1-naphthyl and 2-naphthyl being preferred especially.
An example of a hydrocarbon group may also be a bicyclic or tricyclic hydrocarbon group resulted from a condensation of two to three groups (preferably 2 or more types of the groups) which may be same or different and selected from the group consisting of the alicyclic hydrocarbon groups and the aromatic hydrocarbon groups described above such as 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, dihydrobenzocycloheptenyl, fluorenyl and the like.
A heterocyclic group in xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R may for example be an aromatic heterocyclic group, a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group) containing, as an atom constituting a ring system (ring atom), at least one (preferably 1 to 4, more preferably 1 to 2) atom of 1 to 3 species (preferably 1 to 2 species) of the heteroatoms selected from oxygen, sulfur and nitrogen atoms.
xe2x80x9cAromatic heterocyclic groupxe2x80x9d may for example be a 5- to 6-membered aromatic monocyclic heterocyclic group such as an aromatic monocyclic heterocyclic group (for example, furyl, thienyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like) and a 8- to 12-membered aromatic fused heterocyclic group such as an aromatic fused heterocyclic group (for example, benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, benzokisazolyl, 1,2-benzoisooxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthylidinyl, purinyl, puteridinyl, carbazolyl, xcex1-carbolinyl, xcex2-carbolinyl, xcex3-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiynyl, thianthrenyl, phenathridinyl, phenathrolinyl, indolidinyl, pyrrolo[1,2-b]pyridazinyl, pyrrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl and the like) and the like (preferably a heterocyclic ring formed by a condensation of a 5- to 6-membered aromatic monocyclic heterocyclic group described above with a benzene ring, or a heterocyclic ring formed by a condensation of two same or different heterocyclic rings of 5- to 6-membered aromatic monocyclic heterocyclic groups described above, more preferably a heterocyclic ring formed by a condensation of a 5- to 6-membered aromatic monocyclic heterocyclic group described above, particularly, benzofuranyl, benzopyranyl, benzo[b]thienyl and the like).
xe2x80x9cNon-aromatic heterocyclic groupxe2x80x9d may for example be a 3- to 8-membered (preferred 5- to 6-membered) saturated or non-saturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group) such as oxylanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like, as well as a non-aromatic heterocyclic group formed as a result of a saturation of a part or all of the double bonds of an aromatic monocyclic heterocyclic group or an aromatic fused heterocyclic group described above such as 1,2,3,4-tetrahydroquiolyl, 1,2,3,4-tetrahydroisoquinolyl and the like.
A substituent on xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d and xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R may for example be an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted heterocyclic group, an optionally substituted amino group, an optionally substituted imidoyl group (for example a group represented by Formula xe2x80x94C(Uxe2x80x2)xe2x95x90Nxe2x80x94U wherein each of U and Uxe2x80x2 is a hydrogen atom or a substituent (U is preferably a hydrogen atom)), an optionally substituted amidino group (for example a group represented by Formula xe2x80x94C(NTxe2x80x2Txe2x80x3)xe2x95x90Nxe2x80x94T wherein each of T, Txe2x80x2 and Txe2x80x3 is a hydrogen atom or a substituent (T is preferably a hydrogen atom)), an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, a halogen atom (for example, fluorine, chlorine, iodine and the like, preferably chlorine, bromine and the like), a cyano group, a nitro group, a sulfonic acid-derived acyl group, a carboxylic acid-derived acyl group and the like, and any of these substituent may occur 1 to 5 times (preferably 1 to 3 times) in any possible positions. It may also possible. that xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d and xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by have oxo groups, and when R is benzopyranyl then R may form benzo-xcex1-pyronyl, benzo-xcex3-pyronyl and the like.
An aryl group in xe2x80x9coptionally substituted aryl groupxe2x80x9d as a substituent may for example be a C6-14 aryl group such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like. A substituent on an aryl group mentioned here may for example be a lower alkoxy group (for example a C1-6 alkoxy group such as methoxy, ethoxy), a halogen atom (for example fluorine, chlorine, bromine and iodine), a lower alkyl group (such as a C1-6 alkyl group such as methyl, ethyl and propyl), a lower alkenyl group (for example a C2-6 alkenyl group such as vinyl and allyl), a lower alkynyl group (for example a C2-6 alkynyl group such as ethynyl and propargyl), an optionally substituted amino group, an optionally substituted hydroxyl group, a cyano group, an optionally substituted amidino group, a carboxyl group, a lower alkoxycarbonyl group (for example a C1-6 alkoxycarbonyl group such as methoxycarbonyl and ethoxycarbonyl), an optionally substituted carbamoyl group (for example a carbamoyl group which may be substituted by a C1-6 alkoxy or acyl group (for example, formyl, C2-6 alkanoyl, benzoyl, an optionally halogenated C1-6 alkoxy-carbonyl, an optionally halogenated C1-6 alkyl-sulfonyl, benzenesulfonyl group)) and the like, and any of these substituent may occur 1 to 3 times in any possible positions. xe2x80x9cOptionally substituted amino groupxe2x80x9d, xe2x80x9coptionally substituted hydroxyl groupxe2x80x9d and xe2x80x9coptionally substituted amidino groupxe2x80x9d as substituents are similar to xe2x80x9coptionally substituted amino groupxe2x80x9d, xe2x80x9coptionally substituted hydroxyl groupxe2x80x9d and xe2x80x9coptionally substituted amidino groupxe2x80x9d as substituents which may be possessed by xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d and xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R.
A cycloalkyl group in xe2x80x9coptionally substituted cycloalkyl groupxe2x80x9d as a substituent may for example be a C3-7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A substituent on a cycloalkyl group mentioned here may be similar to those of a substituent on xe2x80x9coptionally substituted aryl groupxe2x80x9d described above and may occur similar times.
A cycloalkenyl group in xe2x80x9coptionally substituted cycloalkenyl groupxe2x80x9d as a substituent may for example be a C3-6 cycloalkenyl group such as cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl, and a substituent on an optionally substituted cycloalkenyl group mentioned here may be similar to those of a substituent on xe2x80x9coptionally substituted aryl groupxe2x80x9d described above and may occur similar times.
An alkyl group in xe2x80x9coptionally substituted alkyl groupxe2x80x9d as a substituent may for example be a C1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl and the like. A substituent on an alkyl group mentioned here may be similar to those of a substituent on xe2x80x9coptionally substituted aryl groupxe2x80x9d described above and may occur similar times.
An alkenyl group in xe2x80x9coptionally substituted alkenyl groupxe2x80x9d as a substituent may for example be a C2-6 alkenyl group such as vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like. A substituent on an alkenyl group mentioned here may be similar to those of a substituent on xe2x80x9coptionally substituted aryl groupxe2x80x9d described above and may occur similar times.
An alkynyl group in xe2x80x9coptionally substituted alkynyl groupxe2x80x9d as a substituent may for example be a C2-6 alkynyl group such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like. A substituent on an alkynyl group mentioned here may be similar to those of a substituent on xe2x80x9coptionally substituted aryl groupxe2x80x9d described above and may occur similar times.
A heterocyclic group in xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d as a substituent may for example be an aromatic heterocyclic group, a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group) containing as an atom constituting a ring system (ring atom) at least one (preferably 1 to 4, more preferably 1 to 2) atom of 1 to 3 species (preferably 1 to 2 species) of the heteroatoms selected from oxygen, sulfur and nitrogen atoms. xe2x80x9cAromatic heterocyclic groupxe2x80x9d may for example be a 5- to 6-membered aromatic monocyclic heterocyclic group such as an aromatic monocyclic heterocyclic group (for example, furyl, thienyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like) and a 8- to 12-membered aromatic fused heterocyclic group such as an aromatic fused heterocyclic group (for example, benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisooxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthylidinyl, purinyl, puteridinyl, carbazolyl, xcex1-carbolinyl, xcex2-carbolinyl, xcex3-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, , thianthrenyl, phenathridinyl, phenathrolinyl, indolidinyl, pyrrolo[1,2-b]pyridazinyl, pyrrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl and the like) and the like (preferably a heterocyclic ring formed by a condensation of a 5- to 6-membered aromatic monocyclic heterocyclic group described above with a benzene ring, or a heterocyclic ring formed by a condensation of two same or different heterocyclic rings of 5- to 6-membered aromatic monocyclic heterocyclic groups described above).
xe2x80x9cNon-aromatic heterocyclic groupxe2x80x9d may for example be a 3- to 8-membered (preferred 5- to 6-membered) saturated or non-saturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group) such as oxylanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like, as well as a non-aromatic heterocyclic group formed as a result of a saturation of a part or all of the double bonds of an aromatic monocyclic heterocyclic group or an aromatic fused heterocyclic group described above such as 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl and the like.
A substituent which may be possessed by xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d as a substituent may for example be a lower alkyl group (for example a C1-5 alkyl group such as methyl, ethyl and propyl), a lower alkenyl group (for example a C2-5 alkenyl group such as vinyl and allyl), a lower alkynyl group (for example a C2-6 alkynyl group such as ethynyl and propargyl), an acyl group (for example a C1-6 alkanoyl group such as formyl, acetyl, propyl and pivaloyl and benzoyl), an optionally substituted amino group, an optionally substituted hydroxyl group, a halogen atom (for example, fluorine, chlorine, bromine, iodine, preferably chlorine, bromine), an optionally substituted imidoyl group, an optionally substituted amidino group and the like.
xe2x80x9cOptionally substituted amino groupxe2x80x9d, xe2x80x9coptionally substituted hydroxyl groupxe2x80x9d, xe2x80x9coptionally substituted imidoyl groupxe2x80x9d and xe2x80x9coptionally substituted amidino groupxe2x80x9d which may be possessed by xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d as a substituent may for example be those similar to xe2x80x9coptionally substituted amino groupxe2x80x9d, xe2x80x9coptionally substituted hydroxyl groupxe2x80x9d, xe2x80x9coptionally substituted imidoyl groupxe2x80x9d and xe2x80x9coptionally substituted amidino groupxe2x80x9d which may be possessed by xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d and xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R.
A substituent on xe2x80x9coptionally substituted amino groupxe2x80x9d, xe2x80x9coptionally substituted imidoyl groupxe2x80x9d, xe2x80x9coptionally substituted amidino groupxe2x80x9d, xe2x80x9coptionally substituted hydroxy groupxe2x80x9d and xe2x80x9coptionally substituted thiol groupxe2x80x9d as substituents which may be possessed by xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d and xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R may for example a lower alkyl group (for example a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl) which may be substituted by a substituent selected from a halogen atom (for example fluorine, chlorine, bromine, iodine) and an optionally halogenated C1-6 alkoxy group (for example methoxy, ethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, trichloromethoxy, 2,2,2-trichloroethoxy), an acyl group (a C1-6 alkanoyl (for example formyl, acetyl, propionyl, pivaloyl), benzoyl), an optionally halogenated C1-6 alkoxy-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl, trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, trichloromethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl), an optionally halogenated C1-6 alkyl-sulfonyl, benzenesulfonyl), a heterocyclic group (those similar to xe2x80x9cheterocyclic groupxe2x80x9d in xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R, preferably pyridyl, more preferably 4-pyridyl), and xe2x80x9camino groupxe2x80x9d in xe2x80x9coptionally substituted amino groupxe2x80x9d as a substituent may be substituted by an optionally substituted imidoyl group (for example a C1-6 alkylimidoyl (for example formyl imidoyl, acetylimidoyl), a C1-6 alkoxyimidoyl, a C1-6 alkylthioimidoyl, amidino) and an amino group which may be substituted by 1 to 2 C1-6 alkyls, or two substituents are taken together with a nitrogen atom to form a cyclic amino group, and in such case such cyclic amino group may for example be a 3- to 8-membered (preferably 5- to 6-membered) cyclic amino group such as 1-azetidinyl; 1-pyrrolidinyl; piperidino; thiomorpholino; morpholino; 1-piperazinyl; 1-piperazinyl; which may have in its 4-position a lower alkyl group (for example a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl), an aralkyl group (for example a C7-10 aralkyl group such as benzyl and phenethyl) and an aryl group (for example a C6-10 aryl group such as phenyl, 1-naphthyl, 2-naphthyl); 1-pyrrolyl; and 1-imidazolyl.
xe2x80x9cOptionally substituted carbamoyl groupxe2x80x9d may for example be a unsubstituted carbamoyl as well as an N-monosubstituted carbamoyl group and an N,N-disubstituted carbamoyl group.
xe2x80x9cN-Monosubstituted carbamoyl groupxe2x80x9d means a carbamoyl group having one substituent on a nitrogen atom, and such substituent may for example be a lower alkyl group (for example a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl), a lower alkenyl group (for example a C2-6 alkenyl group such as vinyl, allyl, isopropenyl, propenyl, butenyl, pentenyl, hexenyl), a cycloalkyl group (for example a C3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), an aryl group (for example a C6-10 aryl group such as phenyl, 1-naphthyl and 2-naphthyl), an aralkyl group (for example a C7-10 aralkyl group such as benzyl and phenethyl, preferably a phenyl-C1-4 alkyl group), an arylalkenyl group (for example a C8-10 arylalkenyl group such as cinnamyl, preferably a phenyl-C2-4 alkenyl group), a heterocyclic group (for example those similar to xe2x80x9cheterocyclic ringxe2x80x9d as a substituent on xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R described above) and the like. Each of such lower alkyl group, a lower alkenyl group, a cycloalkyl group, an aryl group, an aralkyl group, an arylalkenyl group and a heterocyclic group may have a substituent, and such substituent may for example be a hydroxyl group, an optionally substituted amino group [such amino group may have as its substituents one or two groups selected from a lower alkyl group (for example a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl), an acyl group (for example a C1-6 alkanoyl group such as formyl, acetyl, propionyl and pivaloyl as well as benzoyl), a carboxyl group, a C1-6 alkoxy-carbonyl group and the like], a halogen atom (for example fluorine, chlorine, bromine, iodine), a nitro group, a cyano group, a carboxyl group, a C1-6 alkoxy-carbonyl group, a lower alkyl group which may be substituted by 1 to 5 halogen atoms (for example, fluorine, chlorine, bromine, iodine), a lower alkylthio group which may be substituted by 1 to 5 halogen atoms (for example, fluorine, chlorine, bromine, iodine), a lower alkoxy group which may be substituted by 1 to 5 halogen atoms (for example, fluorine, chlorine, bromine, iodine) and the like. A lower alkyl group mentioned above may for example be a C1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, with methyl and ethyl being preferred. A lower alkylthio group mentioned above may for example be a C1-6 alkylthio group such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio, with methylthio and ethylthio being preferred. A lower aikoxy group mentioned above may for example be a C1-6 alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, with methoxy and ethoxy being preferred. Any of these substituent may be same or different and occurs preferably 1 or 2 to 3 times (preferably 1 or 2 times).
xe2x80x9cN,N-Disubstituted carbamoyl groupxe2x80x9d means a carbamoyl group having two substituents on a nitrogen atom, and an example of one of these substituents is similar to a substituent on xe2x80x9cN-monosubstituted carbamoyl groupxe2x80x9d described above, and an example of the other may for example be a lower alkyl group (for example a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl), a C3-6 cycloalkyl group (for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), a C7-10 aralkyl group (for example benzyl, phenethyl, preferably a phenyl-C1-4 alkyl group). Alternatively, two substituents may be taken together with a nitrogen atom to form a cyclic amino group, and in such case a cyclic aminocarbamoyl group may for example be a 3- to 8-membered (preferably 5- to 6-membered) cyclic amino-carbonyl such as 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl as well as piperidinylcarbonyl which may have in its 4-position a lower alkyl group (for example a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl), an aralkyl group (for example a C7-10 aralkyl group such as benzyl and phenethyl), an aryl group (for example a C6-10 aryl group such as phenyl, 1-naphthyl, 2-naphthyl), a hydroxyl group, a C1-6 alkoxyl group, a carboxyl group, a C1-6 alkoxy-carbonyl group and the like, morpholinocarbonyl, thiomorpholinocarbonyl whose sulfur atom may be oxidized, 1-piperazinylcarbonyl as well as 1-piperazinylcarbonyl which may have in its 4-position a lower alkyl group (for example a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl), an aralkyl group (for example a C7-10 aralkyl group such as benzyl and phenethyl), an aryl group (for example a C6-10 aryl group such as phenyl, 1-naphthyl, 2-naphthyl) and the like.
A substituent on xe2x80x9coptionally substituted thiocarbamoyl groupxe2x80x9d and xe2x80x9coptionally substituted sulfamoyl groupxe2x80x9d may for example be a substituent on xe2x80x9coptionally substituted carbamoyl groupxe2x80x9d described above.
An optionally esterified carboxyl group may for example be a free carboxyl group as well as a lower alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group and the like.
xe2x80x9cLower alkoxycarbonyl groupxe2x80x9d may for example be a C1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl and neopentyloxycarbonyl, which a C1-3 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl being preferred.
xe2x80x9cAryloxycarbonyl groupxe2x80x9d may for example be a C7-12 aryloxy-carbonyl group such as phenoxycarbonyl, 1-naphthoxycarbpnyl, 2-naphthoxycarbonyl and the like.
xe2x80x9cAralkyloxycarbonyl groupxe2x80x9d may for example be a C7-10 aralkyloxy-carbonyl group such as benzyloxycarbonyl and phenethyloxycarbony (preferably a C6-10 aryl-C1-4 alkoxy-carbonyl).
Each of such xe2x80x9caryloxycarbonyl groupxe2x80x9d and xe2x80x9caralkoxycarbonyl groupxe2x80x9d may have a substituent, and such substituent may be similar to those of a substituent on an aryl group and an aralkyl group as the examples of a substituent on an N-monosubstituted carbamoyl group described above and may occur similar times.
xe2x80x9cSulfonic acid-derived acyl groupxe2x80x9d as a substituent may for example be a sulfonyl bound to a substituent occurring one time on a nitrogen atom of xe2x80x9cN-monosubstituted carbamoyl groupxe2x80x9d described above, and is preferably an acyl such as a C1-6 alkylsulfonyl including methanesulfonyl and ethanesulfonyl. xe2x80x9cCarboxylic acid-derived acyl groupxe2x80x9d as a substituent may for example be a carbonyl bound to a substituent occurring one time on a nitrogen atom of xe2x80x9cN-monosubstituted carbamoyl groupxe2x80x9d described above, and is preferably an acyl such as a C1-6 alkanoyl such as formyl, acetyl, propionyl and pivaloyl as well as benzoyl.
R is preferably an optionally substituted hydrocarbon group, especially, an aryl group which may be substituted by a halogen atom or a C2-4 alkenyl (preferably a C6-14 aryl group, such as phenyl and 2-naphthyl, which may be substituted by a halogen atom or a C2-4 alkenyl group, more preferably naphthyl which may be substituted by a halogen atom, most preferably 2-naphthyl having a halogen atom in its 6-position).
It is also preferable that R is an optionally substituted heterocyclic group, especially a heterocyclic group which may be substituted by a halogen atom (preferably, benzofuranyl group, benzopyranyl group, more preferably benzopyranyl group).
In Formula shown above, xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1 and R2 or R1xe2x80x2 may for example be one similar to xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R, with an optionally substituted lower (C1-4) alkyl group being preferred.
It is also possible that R1 and R2 are bound to each other to form a ring, and R1 and R2 are bound to each other and taken together with xe2x80x94Nxe2x80x94X1xe2x80x94CDxe2x80x94Nxe2x80x94 to form xe2x80x9coptionally substituted divalent nitrogen-containing heterocyclic groupxe2x80x9d.
Such xe2x80x9cdivalent nitrogen-containing heterocyclic groupxe2x80x9d in xe2x80x9coptionally substituted divalent nitrogen-containing heterocyclic groupxe2x80x9d is a divalent 5- to 8-membered nitrogen-containing heterocyclic group containing two or 3 nitrogen atoms, in addition to carbon atoms, as its atoms constituting a ring system (ring atoms) (preferably a divalent 5- to 8-membered nitrogen-containing heterocyclic group comprising carbon atoms and two nitrogen atoms).
While such xe2x80x9cdivalent nitrogen-containing heterocyclic groupxe2x80x9d has an oxo group or a thioxo group on a carbon atom adjacent to the nitrogen atom to which a substituent represented by R2 is bound and forms a xe2x80x9cdivalent 5- to 8-membered nitrogen-containing cyclic amide groupxe2x80x9d, such xe2x80x9cdivalent 5- to 8-membered nitrogen-containing cyclic amide groupxe2x80x9d may for example be 2-oxoimidazolidine-1,3-diyl, 2-oxoimidazolone-1,3-diyl, 2-oxopiperazine-1,4-diyl, 2-oxo-1,2,3,4-tetrahydropyrazine-1,4-diyl, 2-oxohomopiperazine-1,4-diyl, 5-oxohomopiperazine-1,4-diyl, 2-oxo-1,4-diazacyclooctane-1,4-diyl, 5-oxo-1,4-diazacyclooctane-1,4-diyl, 2-oxo-1,5-diazacyclooctane-1,5-diyl, 5-oxo-2,3-dehydrohomopiperazine-1,4-diyl, 3-oxo-1,2,4-triazacyclohexane-1,4-diyl, 3-oxo-1,2,3,4-tetrahydro-1,2,4xe2x80x9ctriaziyne-1,4-diyl, 6-oxo-1,2,4-triazacyclohexane-1,4-diyl and the like.
A substituent on xe2x80x9cdivalent nitrogen-containing heterocyclic groupxe2x80x9d in xe2x80x9coptionally substituted divalent nitrogen-containing heterocyclic groupxe2x80x9d described above, in addition to one oxo group or thioxo group, may for example be an optionally substituted hydroxyl group, an optionally substituted mercapto group, a halogen atom (for example, chlorine, bromine, iodine), a nitro group, a cyano group, an oxo group, an optionally substituted amino group, an optionally substituted lower alkyl group, an optionally substituted lower alkylidene group, an optionally substituted lower aralkylidene group, a lower alkoxy group which may be substituted by 1 to 5 halogen atoms (for example, fluorine, chlorine, bromine, iodine), an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group (preferably, an optionally substituted lower alkyl group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group and the like), and any of these substituents may occur 1 to 3 times (preferably 1 to 2 times) in any possible positions.
While a substituent on xe2x80x9coptionally substituted amino groupxe2x80x9d mentioned here may for example be 1 to 2 optionally substituted alkyl groups, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamnoyl group, an optionally esterified carboxyl group, a sulfonic acid-derived acyl group and a carboxylic acid-derived acyl group, xe2x80x9coptionally substituted alkyl groupxe2x80x9d, xe2x80x9coptionally substituted carbamoyl groupxe2x80x9d, xe2x80x9coptionally substituted thiocarbamoyl groupxe2x80x9d, xe2x80x9coptionally substituted sulfamoyl groupxe2x80x9d, xe2x80x9coptionally esterified carboxyl groupxe2x80x9d, xe2x80x9csulfonic acid-derived acyl groupxe2x80x9d and xe2x80x9ccarboxylic acid-derived acyl groupxe2x80x9d mentioned here may for example be those similar to xe2x80x9coptionally substituted alkyl groupxe2x80x9d, xe2x80x9coptionally substituted carbamoyl groupxe2x80x9d, xe2x80x9coptionally su bst ituted thiocarbamoyl groupxe2x80x9d, xe2x80x9coptionally substituted sulfamoyl groupxe2x80x9d, xe2x80x9coptionally esterified carboxyl groupxe2x80x9d, xe2x80x9csulfonic acid-derived acyl groupxe2x80x9d and xe2x80x9ccarboxylic acid-derived acyl groupxe2x80x9d as substituents on xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R described above, and a preferred example of xe2x80x9coptionally substituted amino groupxe2x80x9d is an amino group which may have 1 to 2 substituents selected from (1) a lower (C1-6)alkylgroup such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl, (2) a mono- or di-lower (C1-6)alkylcarbamoyl group, (3) a (C1-6)alkylsulfonyl group such as methanesulfonyl and ethanesulfonyl, (4) a (C1-6)alkanoyl such as formyl, acetyl, propionyl and pivaloyl, and (5) benzoyl.
A lower alkyl group in xe2x80x9coptionally substituted lower alkyl groupxe2x80x9d may for example be a C1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like, with methyl and ethyl being preferred especially. Its substituent may for example be a halogen atom (for example, fluorine, chlorine, bromine and iodine), an amino group which may be substituted by a C1-6 alkyl or acyl group (e.g., formyl, C26 alkanoyl, benzoyl, an optionally halogenated C1-6 alkoxy-carbonyl, an optionally halogenated C1-6 alkyl-sulfonyl, benzenesulfonyl), a carboxyl group, a C1-6 alkoxy-carbonyl group, a carbamoyl group which may be substituted by a C1-6 alkyl or acyl group (e.g., formyl, C2-6 alkanoyl, benzoyl, an optionally halogenated C1-6 alkoxy-carbonyl, an optionally halogenated C1-5 alkyl-sulfonyl, benzenesulfonyl), a hydroxyl group, a C6-10 aryl, a C6-10 aryloxy, a C6-10 aryl-C1-4 alkoxy and the like, and any of these substituents may occur 1 to 5 times (preferably 1 to 2 times) in any possible positions.
xe2x80x9cOptionally substituted lower alkylidene groupxe2x80x9d may for example be a C1-6 alkylidene such as methylidene and ethylidene, and its substituent may for example be a halogen atom (for example, fluorine, chlorine, bromine and iodine), an amino group, a carboxyl group and a hydroxyl group, and any of these substituents may occur 1 to 5 times (preferably 1 to 2 times) in any possible positions.
xe2x80x9cOptionally substituted lower aralkylidene groupxe2x80x9d may for example be a C6-10 aryl-C1-4 alkylidene such as benzylidene, and its substituent may for example be a halogen atom (for example, fluorine, chlorine, bromine and iodine), an amino group, a carboxyl group and a hydroxyl group, and any of these substituents may occur 1 to 5 times (preferably 1 to 2 times) in any possible positions.
A lower alkoxy group in xe2x80x9clower alkoxy group which may be substituted by a halogen and the likexe2x80x9d may for example be a C1-6 alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, with methoxy and ethoxy being preferred especially. Such lower alkoxy group may have a substituent similar to xe2x80x9clower alkyl groupxe2x80x9d in xe2x80x9coptionally substituted lower alkyl groupxe2x80x9d which may be possessed as a substituent by xe2x80x9coptionally substituted divalent nitrogen-containing heterocyclic groupxe2x80x9d described above.
xe2x80x9cOptionally esterified carboxyl groupxe2x80x9d may for example be one similar to an optionally esterified carboxyl group as a substituent on xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R described above.
xe2x80x9cOptionally substituted carbamoyl groupxe2x80x9d, xe2x80x9coptionally substituted thiocarbamoyl groupxe2x80x9d and xe2x80x9coptionally substituted sulfamoyl groupxe2x80x9d may for example be those similar to an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group and an optionally substituted sulfamoyl group as substituents on xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R described above.
A substituent which may be possessed by xe2x80x9chydroxyl groupxe2x80x9d and xe2x80x9cmercapto groupxe2x80x9d in xe2x80x9coptionally substituted hydroxyl groupxe2x80x9d and xe2x80x9coptionally substituted mercapto groupxe2x80x9d as substituents which may be possessed by xe2x80x9cdivalent nitrogen-containing heterocyclic groupxe2x80x9d described above may for example be an optionally substituted lower alkyl group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, a sulfonic acid-derived acyl group, a carboxylic group-derived acyl group and the like. Such lower alkyl group may for example be a C1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, and a substituent which may be possessed by this lower alkyl group may for example be a halogen atom (for example, fluorine, chlorine, bromine and iodine), an optionally substituted aryl group [for example phenyl or naphthyl which may be substituted by a halogen atom (for example, fluorine, chlorine, bromine and iodine), a lower alkyl group (e.g., a C1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl), a lower alkoxy group (e.g., C1-6 alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy) and the like], an optionally substituted hydroxyl group (e.g., one similar to an optionally substituted hydroxyl group as a substituent on xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R described abovexe2x80x9d), an optionally substituted thiol group (e.g., one similar to an optionally substituted thiol group as a substituent on xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R described abovexe2x80x9d), an optionally substituted amino group (e.g., one similar to an optionally substituted amino group as a substituent on xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R described abovexe2x80x9d), an optionally esterified carboxyl group (e.g., one similar to an optionally esterified carboxyl group as a substituent on xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R described abovexe2x80x9d) and the like. In xe2x80x9coptionally substituted mercapto groupxe2x80x9d, a sulfur atom may be oxidized, and may have a structure represented for example by S(O)k wherein k is an integer of 0 to 2.
xe2x80x9cOptionally esterified carboxyl groupxe2x80x9d, xe2x80x9coptionally substituted carbamoyl groupxe2x80x9d, xe2x80x9coptionally substituted thiocarbamoyl groupxe2x80x9d, xe2x80x9coptionally substituted sulfamoyl groupxe2x80x9d, xe2x80x9csulfonic acid-derived acyl groupxe2x80x9d and xe2x80x9ccarboxylic group-derived acyl groupxe2x80x9d as substituents which may be possessed by xe2x80x9chydroxyl groupxe2x80x9d and xe2x80x9cmercapto groupxe2x80x9d in xe2x80x9coptionally substituted hydroxyl groupxe2x80x9d and xe2x80x9coptionally substituted mercapto groupxe2x80x9d as substituents which may be possessed by xe2x80x9cdivalent nitrogen-containing heterocyclic groupxe2x80x9d described above may for example be those similar to xe2x80x9coptionally esterified carboxyl groupxe2x80x9d, xe2x80x9coptionally substituted carbamoyl groupxe2x80x9d, xe2x80x9coptionally substituted thiocarbamoyl groupxe2x80x9d, xe2x80x9coptionally substituted sulfamoyl groupxe2x80x9d, xe2x80x9csulfonic acid-derived acyl groupxe2x80x9d and xe2x80x9ccarboxylic group-derived acyl groupxe2x80x9d as substituents on xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R described above.
A preferred xe2x80x9cdivalent nitrogen-containing heterocyclic groupxe2x80x9d described above may for example be a group represented by Formula: 
wherein X3 is an optionally substituted C1-2 alkylene, X4 is an optionally substituted C1-3 alkylene and D is an oxygen atom or a sulfur atom, and more preferably a group represented by Formula: 
wherein n is 1 or 2, mxe2x80x3 is 1 or 2, R8 is a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted mercapto group, a nitro group, a cyano group, an optionally substituted amino group, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group or an optionally substituted sulfamoyl group (preferably, a hydrogen atom, an optionally substituted lower alkyl group, a cyano group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group or an optionally substituted thiocarbamoyl group), and D is an oxygen atom or a sulfur atom.
xe2x80x9cC1-2 Alkylenexe2x80x9d in xe2x80x9coptionally substituted C1-2 alkylenexe2x80x9d represented by X3 may for example be a straight alkylene such as methylene and ethylene, and such xe2x80x9cC1-2 alkylenexe2x80x9d may have a group similar to a substituent which may be possessed by xe2x80x9cdivalent nitrogen-containing heterocyclic groupxe2x80x9d in xe2x80x9coptionally substituted divalent nitrcgen-containing heterocyclic groupxe2x80x9d described above. xe2x80x9cC1-3 Alkylenexe2x80x9d in xe2x80x9coptionally substituted C1-3 alkylene represented by X4 may for example be a straight alkylene such as methylene, ethylene and propylene, and such xe2x80x9cC1-3 alkylenexe2x80x9d may have a group similar to a substituent which may be possessed by xe2x80x9cdivalent nitrogen-containing heterocyclic groupxe2x80x9d in xe2x80x9coptionally substituted divalent nitrogen-containing heterocyclic groupxe2x80x9d described above.
In the formula described above, xe2x80x9coptionally substituted hydroxyl groupxe2x80x9d, xe2x80x9coptionally substituted mercapto groupxe2x80x9d, xe2x80x9cnitro groupxe2x80x9d, xe2x80x9ccyano groupxe2x80x9d, xe2x80x9coptionally substituted amino groupxe2x80x9d, xe2x80x9coptionally substituted lower alkyl groupxe2x80x9d, xe2x80x9coptionally substituted lower alkoxy groupxe2x80x9d, xe2x80x9coptionally esterified carboxyl groupxe2x80x9d, xe2x80x9coptionally substituted carbamoyl groupxe2x80x9d, xe2x80x9coptionally substituted thiocarbamoyl groupxe2x80x9d and xe2x80x9coptionally substituted sulfamoyl groupxe2x80x9d may for example those similar to xe2x80x9coptionally substituted hydroxyl groupxe2x80x9d, xe2x80x9coptionally substituted mercapto groupxe2x80x9d, xe2x80x9cnitro groupxe2x80x9d, xe2x80x9ccyano groupxe2x80x9d, xe2x80x9coptionally substituted amino groupxe2x80x9d, xe2x80x9coptionally substituted lower alkyl groupxe2x80x9d, xe2x80x9coptionally substituted lower alkoxy groupxe2x80x9d, xe2x80x9coptionally esterified carboxyl groupxe2x80x9d, xe2x80x9coptionally substituted carbamoyl groupxe2x80x9d, xe2x80x9coptionally substituted thiocarbamoyl groupxe2x80x9d and xe2x80x9coptionally substituted sulfamoyl groupxe2x80x9d which may be possessed as substituents by xe2x80x9cdivalent nitrogen-containing heterocyclic groupxe2x80x9d in xe2x80x9coptionally substituted divalent nitrogen-containing heterocyclic groupxe2x80x9d described above.
xe2x80x9cDivalent nitrogen-containing heterocyclic groupxe2x80x9d described above is preferably a group represented by Formula: 
wherein n is 1 or 2 and m is 2 or 3.
In the formula shown above, m is preferably 2, and n is preferably 1.
Most preferably, xe2x80x9cdivalent nitrogen-containing heterocyclic groupxe2x80x9d described above is 2-oxopiperazine-1,4-diyl.
It is also possible that a substituent on X1 and R2 are bound to each other and a divalent group represented by xe2x80x94X1xe2x80x94CDxe2x80x94N(R2)xe2x80x94 forms xe2x80x9coptionally substituted divalent nitrogen-containing heterocyclic groupxe2x80x9d. xe2x80x9cDivalent nitrogen-containing heterocyclic groupxe2x80x9d in this xe2x80x9coptionally substituted divalent nitrogen-containing heterocyclic groupxe2x80x9d may for example be a divalent 5- to 8-membered nitrogen-containing heterocyclic group containing 1 or 3 nitrogen atoms, in addition to carbon atoms, as its atoms constituting a ring system (ring atoms) (preferably a divalent 5- to 7-membered nitrogen-containing heterocyclic group comprising carbon atoms and one nitrogen atom).
While such xe2x80x9cdivalent nitrogen-containing heterocyclic groupxe2x80x9d has an oxo group or a thioxo group -on a carbon atom adjacent to the nitrogen atom to which a substituent represented by R2 is bound and forms a xe2x80x9cdivalent 5- to 8-membered nitrogen-containing cyclic amide groupxe2x80x9d, a substituent on xe2x80x9cdivalent nitrogen-containing heterocyclic groupxe2x80x9d in such xe2x80x9coptionally substituted divalent nitrogen-containing heterocyclic groupxe2x80x9d may for example be one similar to a substituent which may be possessed by xe2x80x9cdivalent nitrogen-containing heterocyclic groupxe2x80x9d in xe2x80x9coptionally substituted divalent nitrogen-containing heterocyclic groupxe2x80x9d formed by binding R1 and R2 to each other.
xe2x80x9cDivalent nitrogen-containing heterocyclic groupxe2x80x9d formed by binding a substituent on X1 and R2 to each other may for example be xe2x80x9coptionally substituted divalent nitrogen-containing heterocyclic groupxe2x80x9d which may be a group represented by Formula: 
wherein X5 is a bond or an optionally substituted methylene, X6 is an optionally substituted C2-3 alkylene and D is an oxygen atom or a sulfur atom.
xe2x80x9cMethylenexe2x80x9d represented by X5 shown here may have a group similar to a substituent which may be possessed by xe2x80x9cdivalent nitrogen-containing heterocyclic groupxe2x80x9d in xe2x80x9coptionally substituted divalent nitrogen-containing heterocyclic groupxe2x80x9d described above. xe2x80x9cC2-3 Alkylenexe2x80x9d in xe2x80x9coptionally substituted C2-3 alkylenexe2x80x9d represented by X6 may for example be a straight alkylene such as ethylene and propylene, and such xe2x80x9cC2-3 alkylenexe2x80x9d may have a group similar to a substituent which may be possessed by xe2x80x9cdivalent nitrogen-containing heterocyclic groupxe2x80x9d in xe2x80x9coptionally substituted divalent nitrogen-containing heterocyclic groupxe2x80x9d described above.
Among those listed above, a group represented by Formula: 
wherein nxe2x80x2 is 0 or 1 and mxe2x80x2 is 2 or 3 is preferred.
In the formula shown above, mxe2x80x2 is preferably 2, and nxe2x80x2 is preferably 0.
Most preferably, xe2x80x9cdivalent nitrogen-containing heterocyclic groupxe2x80x9d described above is 2-pyrrolidone-1,3-diyl.
xe2x80x9cAlkylene groupxe2x80x9d in xe2x80x9coptionally substituted alkylene groupxe2x80x9d represented by X1 and X2 may for example be a straight lower (C1-6) alkylene such as methylene, ethylene, propylene, butylene and pentylene, with a C1-4 alkylene such as methylene and ethylene being preferred. A substituent on xe2x80x9calkylene groupxe2x80x9d may for example be an optionally substituted lower alkyl group [one similar to xe2x80x9coptionally substituted lower alkyl groupxe2x80x9d as a substituent on xe2x80x9coptionally substituted divalent nitrogen-containing heterocyclic groupxe2x80x9d described above, preferably, a lower alkyl group (for example a C1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl)], an optionally substituted carbamoyl group [one similar to xe2x80x9coptionally substituted carbamoyl groupxe2x80x9d as a substituent on xe2x80x9coptionally substituted divalent nitrogen-containing heterocyclic groupxe2x80x9d described above, preferably, a carbamoyl group, a N-monolower(C1-6) alkylcarbamoyl group, N,N-dilower(C1-6) alkylcarbamoyl group and the like], a cyano group, a halogen atom (for example, fluorine, chlorine, bromine, iodine), a hydroxyl group, an optionally esterified carboxyl group (such as one similar to xe2x80x9coptionally esterified carboxyl groupxe2x80x9d as a substituent on xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R) and the like, and any of these substituent may occur 1 to 3 times in any possible positions.
xe2x80x9cOptionally substituted imino groupxe2x80x9d represented by X1 and X2 may for example be a group represented by Formula xe2x80x94N(R4)xe2x80x94 wherein R4 denotes a hydrogen atom or a substituent, and this R4 is preferably a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group (preferably a hydrogen atom, an optionally substituted hydrocarbon group) and the like.
In the formula shown above, xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R4 may for example be one similar to xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R.
In the formula shown above, xe2x80x9cacyl groupxe2x80x9d represented by R1 may be one similar to xe2x80x9csulfonic acid-derived acyl groupxe2x80x9d and xe2x80x9ccarboxylic acid-derived acyl groupxe2x80x9d as substituents on xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R described above, it is preferably formyl, an optionally substituted lower (C2-5)alkanoyl group and the like, with a lower (C2-5)alkanoyl group being more preferred.
In the formula shown above, X1 is preferably methylene and X2 is preferably a bond.
In the formula shown above, D is an oxygen atom or a sulfur atom (preferably an oxygen atom).
In the formula shown above, A is xe2x80x94N(R3)xe2x80x94Yxe2x80x94 or xe2x80x94Nxe2x95x90Yxe2x80x94, R3 is a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group, and Y is an optionally substituted linear hydrocarbon group or an optionally substituted cyclic group.
While xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R3 may for example be one similar to xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R and xe2x80x9cacyl groupxe2x80x9d represented by R3 may for example be one similar to xe2x80x9csulfonic acid-derived acyl groupxe2x80x9d and xe2x80x9ccarboxylic acid-derived acyl groupxe2x80x9d as substituents on xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R described above, R3 is preferably a hydrogen atom, an optionally substituted lower (C1-4)alkyl group, formyl, an optionally substituted lower (C2-5)alkanoyl group and the like, and more preferably hydrogen atom, an optionally substituted lower (C1-4)alkyl group and the like.
xe2x80x9cLinear hydrocarbon groupxe2x80x9d in xe2x80x9coptionally substituted linear hydrocarbon groupxe2x80x9d represented by Y may for example be a divalent or trivalent group formed by removing 1 to 2 hydrogen atoms from one carbon atom in xe2x80x9cstraight or branched (preferably straight) aliphatic hydrocarbon groupxe2x80x9d as xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R, and is typically an optionally substituted C1-6 alkylene group (such as one similar to xe2x80x9coptionally substituted alkylene groupxe2x80x9d represented by X1 and X2 described above), a group represented by Formula xe2x95x90CHxe2x80x94(CH2)kxe2x80x94 wherein k is an integer of 0 to 5 which may have a substituent on any carbon atom, and the like.
A substituent which may be possessed by xe2x80x9clinear hydrocarbon groupxe2x80x9d as xe2x80x9coptionally substituted linear hydrocarbon groupxe2x80x9d represented by Y may for example be an optionally substituted lower alkyl group [one similar to xe2x80x9coptionally substituted lower alkyl groupxe2x80x9d as a substituent on xe2x80x9coptionally substituted divalent nitrogen-containing heterocyclic groupxe2x80x9d described above, preferably, a lower alkyl group (for example a C1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl)], an optionally substituted carbamoyl group [one similar to xe2x80x9coptionally substituted carbamoyl groupxe2x80x9d as a substituent on xe2x80x9coptionally substituted divalent nitrogen-containing heterocyclic groupxe2x80x9d described above, preferably, a carbamoyl group, a N-monolower(C1-6)alkylcarbamoyl group, N,N-dilower(C1-6)alkylcarbamoyl group and the like], a cyano group, a halogen atom (for example, fluorine, chlorine, bromine, iodine), a hydroxyl group, an optionally esterified carboxyl group (such as one similar to xe2x80x9coptionally esterified carboxyl groupxe2x80x9d as a substituent on xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R) and the like, and any of these substituent may occur 1 to 3 times in any possible positions.
xe2x80x9cLinear hydrocarbon groupxe2x80x9d in xe2x80x9coptionally substituted linear hydrocarbon groupxe2x80x9d (preferably an optionally substituted C1-6 alkylene group) represented by Y may undergo a substitution of any methylene group by an oxo group to form a carbonyl group, and may typically be a group represented by Formula xe2x80x94(Cxe2x95x90O)xe2x80x94CH2xe2x80x94 formed as a result of a substitution of a methylene group in xe2x80x94CH2xe2x80x94CH2xe2x80x94 by an oxo group.
A substituent on xe2x80x9coptionally substituted cyclic groupxe2x80x9d represented by Y is one similar to a substituent on xe2x80x9cdivalent nitrogen-containing heterocyclic groupxe2x80x9d described above.
xe2x80x9cCyclic groupxe2x80x9d in xe2x80x9coptionally substituted cyclic groupxe2x80x9d represented by Y may for example be a divalent or trivalent cyclic hydrocarbon group or heterocyclic group (preferably heterocyclic groupxe2x80x9d. xe2x80x9cHydrocarbon groupxe2x80x9d as xe2x80x9ccyclic groupxe2x80x9d in xe2x80x9coptionally substituted cyclic groupxe2x80x9d represented by Y may for example be a saturated or unsaturated, cyclic, divalent or trivalent hydrocarbon group.
A saturated cyclic divalent hydrocarbon group mentioned here may for example be a group obtained by removing one hydrogen atom in any position (preferably on a different carbon atom, more preferably on the farthest carbon atom) of a cycloalkyl group (for example, a C3-9 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl, preferably a C5-7 cycloalkyl, more preferably cyclohexyl) (for example, a C5-7 cycloalkylene, preferably, 1,4-cyclohexylene).
An unsaturated cyclic divalent hydrocarbon group mentioned here may for example be a group obtained by removing one hydrogen atom in any position (preferably on a different carbon atom, more preferably on the farthest carbon atom) of a cycloalkenyl group (for example, a C3-6 cycloalkenyl group such as 2-cyclopenten-2-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl and 1-cyclopenten-1-yl), a cycloalkadienyl group (for example, a C4-6 cycloalkadienyl group such as 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl and 2,5-cyclohexadien-1-yl), an aryl group (for example, a C6-10 aryl group such as phenyl and naphthyl, preferably phenyl), with phenylene being preferred and 1,4-phenylene being particularly preferred.
Such xe2x80x9cdivalent hydrocarbon groupxe2x80x9d is preferably a C5-7 cycloalkylene (preferably 1,4-cyclohexylene), phenylene (preferably 1,4-phenylene) and the like.
xe2x80x9cSaturated or unsaturated cyclic trivalent hydrocarbon groupxe2x80x9d mentioned here may for example be a group formed by removing one hydrogen atom on any carbon atom in which xe2x80x9csaturated or unsaturated cyclic divalent hydrocarbon groupxe2x80x9d mentioned here has a bond.
xe2x80x9cDivalent heterocyclic groupxe2x80x9d as xe2x80x9ccyclic groupxe2x80x9d in xe2x80x9coptionally substituted cyclic groupxe2x80x9d represented by Y may for example be a 5- to 6-membered divalent aromatic heterocyclic group, saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group) containing at least one (preferably 1 to 3, more preferably 1 to 2) atom of 1 to 3 species (preferably 1 to 2 species) of the heteroatoms selected from oxygen, sulfur and nitrogen atoms as an atom constituting a ring system (ring atom) in addition to carbon atoms.
xe2x80x9cDivalent aromatic heterocyclic groupxe2x80x9d may for example be a divalent group obtained by removing 2 hydrogen atoms from 2 different ring atoms of a 5-membered aromatic heterocyclic group such as thiophene, pyrrole, oxazole, isooxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole and 1,2,4-triazole and also of a 6-membered aromatic heterocyclic group such as pyridine, :2 pyridazine, pyrimidine, 1,2,4-triazine and 1,3,5-triazine.
xe2x80x9cDivalent non-aromatic heterocyclic groupxe2x80x9d may for example be a 5- to 6-membered saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group) such as pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, morpholin, thiomorpholin and piperazine.
xe2x80x9cTrivalent heterocyclic groupxe2x80x9d as xe2x80x9ccyclic groupxe2x80x9d of xe2x80x9coptionally substituted cyclic groupxe2x80x9d represented by Y may for example be a group formed by adding one bond to any atom in which xe2x80x9cdivalent non-aromatic heterocyclic groupxe2x80x9d described above has a bond.
Y is preferably an optionally substituted phenylene, an optionally substituted piperidine and the like.
In the formula shown above, A is preferably a group represented by Formula: 
Z is (1) an optionally substituted amino group, (2) an optionally substituted imidoyl group or (3) an optionally substituted nitrogen-containing heterocyclic group.
A substituent on xe2x80x9coptionally substituted amino group represented by Z may for example be one similar to xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d and xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R described above or two such substituents are taken together with a nitrogen atom to form a cyclic amino group, and in such case such cyclic amino group may for example be a 3- to 8-membered (preferably 5- to 6-membered) cyclic amino group such as 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl as well as 1-piperazinyl which may have in its 4-position a lower alkyl group (for example a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl), an aralkyl group (for example a C7-10 aralkyl group such as benzyl and phenethyl) and an aryl group (for example a C6-10 aryl group such as phenyl, 1-naphthyl, 2-naphthyl), and such cyclic amino group may have a substituent similar to those of a substituent on bkoptionally substituted hydrocarbon groupxe2x80x9d represented by R described above which may occur similar times.
Also when xe2x80x9coptionally substituted hydrocarbon * groupxe2x80x9d as a substituent on xe2x80x9camino group which may be substituted by an optionally substituted hydrocarbon groupxe2x80x9d represented by Z contains xe2x80x9coptionally substituted imino groupxe2x80x9d in its a-position, then xe2x80x9coptionally substituted amino groupxe2x80x9d represented by Z forms an amino group substituted by xe2x80x9coptionally substituted imidoyl groupxe2x80x9d represented below by Z, and a group represented by Formula xe2x80x94N(Rxe2x80x3)xe2x80x94C(Rxe2x80x2)xe2x95x90Nxe2x80x94Rxe2x80x2xe2x80x3 wherein Rxe2x80x3 is a hydrogen bond or an optionally substituted hydrocarbon group, Rxe2x80x2xe2x80x3 is a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group or a carboxylic acid-derived acyl group, Rxe2x80x2 is a hydrogen atom, an optionally substituted hydrocarbon group, a carboxylic acid-derived acyl group, an optionally substituted amino group, an optionally substituted mercapto group or an optionally substituted hydroxyl group is included in xe2x80x9coptionally substituted amino groupxe2x80x9d represented by Z. Also when R1 is a mercapto group or a hydroxyl group and Rxe2x80x3 is a hydrogen atom in xe2x80x9coptionally substituted imidoyl groupxe2x80x9d, such xe2x80x9coptionally substituted imidoyl groupxe2x80x9d may each be a group represented by Formula xe2x80x94C(xe2x95x90O)xe2x80x94NH2 or xe2x80x94C(xe2x95x90S)xe2x80x94NH2.
In the formula shown above, xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by Rxe2x80x2xe2x80x3, Rxe2x80x2 and Rxe2x80x3 may for example be one similar to xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R described above, xe2x80x9ccarboxylic acid-derived acyl groupxe2x80x9d represented by Rxe2x80x2xe2x80x3 and Rxe2x80x2 may for example be one similar to xe2x80x9ccarboxylic acid-derived acyl groupxe2x80x9d as a substituent which may be possessed by xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R described above, xe2x80x9coptionally substituted hydroxyl groupxe2x80x9d represented by Rxe2x80x2 may for example be one similar to xe2x80x9coptionally substituted hydroxyl groupxe2x80x9d as a substituent which may be possessed by xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R described above, xe2x80x9coptionally substituted amino groupxe2x80x9d represented by Rxe2x80x2 may for example be one similar to xe2x80x9coptionally substituted amino groupxe2x80x9d as a substituent which may be possessed by xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R described above or an amino group which may have 1 to 2 xe2x80x9coptionally substituted hydrocarbon groupsxe2x80x9d represented by R described above. A compound represented by Formula (I) wherein Rxe2x80x2xe2x80x3 is a carboxylic acid-derived acyl group is useful as a prodrug for a compound in which Rxe2x80x2xe2x80x3 is a hydrogen atom.
While xe2x80x9ccarboxylic acid-derived acyl groupxe2x80x9d represented by Rxe2x80x2xe2x80x3 may for example be one similar to xe2x80x9ccarboxylic acid-derived acyl groupxe2x80x9d as a substituent which may be possessed by xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R described above, xe2x80x9ccarboxylic acid-derived acyl groupxe2x80x9d represented by R may be an optionally esterified carboxyl group such as a group represented by Formula-COORxe2x80x3xe2x80x3 wherein Rxe2x80x3xe2x80x3 is an optionally substituted hydrocarbon group.
xe2x80x9cOptionally substituted hydrocarbon groupxe2x80x9d represented by Rxe2x80x3xe2x80x3 may for example be one similar to xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R described above.
A preferred example of xe2x80x9chydrocarbon groupxe2x80x9d in xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by Rxe2x80x3xe2x80x3 is C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl, C6-10 aryl, C6-10 aryl-C1-4 alkyl and the like. A substituent which may be possessed by such xe2x80x9chydrocarbon groupxe2x80x9d may for example be similar to a substituent which may be possessed by xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1 described above and may occur similar times.
A group represented by Formula xe2x80x94COORxe2x80x3xe2x80x3 may for example be a C1-6 alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl), a C1-6 alkanoyloxy-C1-6 alkoxy-carbonyl group (e.g., pivaloyloxymethoxycarbonyl, 1-(acetoxy)ethoxycarbonyl, acetoxy-tert-butoxycarbonyl), a C1-6 alkoxy-carbonyloxy-C1-6 alkoxy-carbonyl group (e.g., ethoxycarbonyloxymethoxycarbonyl), a 5-C1-4 alkyl-2-oxo-dioxolen-4-yl-C1-6 alkoxy-carbonyl group (e.g., 5-methyl-2-oxo-dioxolen-4-ylmethoxycaronyl) and the like.
More typically, xe2x80x9coptionally substituted amino groupxe2x80x9d represented by Formula Z may for example be an amino group, a mono- or di-lower (C1-6)alkylamino group which may further be substituted by a C6-10 aryl group (preferably phenyl) (for example, methylamino, ethylamino, benzylamino, dimethylamino, diethylamino, diisobutylamino, diisopropylamino, N-ethyl-t-butylamino, benzylmethylamino), a group represented by Formula xe2x80x94N(Rxe2x80x3)xe2x80x94C(Rxe2x80x2)xe2x95x90Nxe2x80x94Rxe2x80x2xe2x80x3 wherein Rxe2x80x3 is a hydrogen atom or an optionally substituted hydrocarbon group (preferably a hydrogen atom or a lower (C1-6)alkyl group), Rxe2x80x2xe2x80x3 is a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group or a carboxylic acid-derived acyl group (preferably a hydrogen atom or a carboxylic acid-derived acyl group), Rxe2x80x2 is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted amino group, an optionally substituted mercapto group or an optionally substituted hydroxyl group (preferably a hydrogen atom, a lower (C1-6)alkyl group, an amino group or a mono- or di-lower (C1-6)alkylamino group (for example, a guanidino group, a formimidoylamino group, an acetoimidoylamino group), a 5- to 6-membered cyclic amino group (for example piperidino group) and the like. xe2x80x9cOptionally substituted imidoyl groupxe2x80x9d represented by Z may for example be a group represented by Formula xe2x80x94C(Rxe2x80x2)xe2x95x90Nxe2x80x94Rxe2x80x2xe2x80x3 wherein each symbol is defined as described above.
When Rxe2x80x2 mentioned here represents an optionally substituted amino group (preferably, amino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, hydrazino, piperidino, piperazino, morpholino, thiomorpholino), then xe2x80x9coptionally substituted imidoyl groupxe2x80x9d represented by Z forms an optionally substituted amidino group. Such optionally substituted amidino group may typically be an amidino group which may be substituted by one to two lower (C1-6)alkyl groups, lower (C1-6)alkanoyl groups, benzoyl groups and the like (for example, amidino, N-methylamidino, N-ethylamidino, N-propylamidino, N,Nxe2x80x2-dimethylamidino, N,Nxe2x80x2-diethylamidino, N-methyl-Nxe2x80x2-diethylamidino, N-formylamidino, N-acetylamidino) and the like. A preferred example of Rxe2x80x2xe2x80x3 described above is hydrogen, a lower alkyl group (for example a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl), an acyl group (for example a C1-6 alkanoyl such as formyl, acetyl, propionyl, pivaloyl); benzoyl; a C1-8 alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl; a C7-10 aralkyloxycarbonyl such as benzyloxycarbonyl, phenethyloxycarbonyl; a hydroxyl group and the like, while a preferred example of Rxe2x80x2 is hydrogen, a lower alkyl group (for example a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl), an optionally substituted amino group (for example an amino group which may be substituted by one or two, same or different lower alkyl groups (for example a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl) or an acyl group (for example a C1-6 alkanoyl such as formyl, acetyl, propionyl, pivaloyl, benzoyl), a hydrazino group, a 5- to 6-membered cyclic amino group (for example, piperidino, thiomorpholino, morpholino, piperazino), a hydroxyl group, a lower alkoxy group (for example, a C1-6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy), a mercapto group, a lower alkylthio group (for example, a C1-6 alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio) and the like.
In the formula shown above, Rxe2x80x2xe2x80x3 is preferably hydrogen.
In the formula shown above, Rxe2x80x2 is preferably hydrogen, a lower alkyl group or an optionally substituted amino group, with a lower alkyl group or an optionally substituted amino group being more preferred and an optionally substituted amino group (preferably amino which may be substituted by a C1-4 alkyl) being particularly preferred.
xe2x80x9cNitrogen-containing heterocyclic groupxe2x80x9d in xe2x80x9coptionally substituted nitrogen-containing heterocyclic groupxe2x80x9d represented by Z may for example be an aromatic nitrogen-containing heterocyclic group and saturated or unsaturated non-aromatic nitrogen-containing heterocyclic group (aliphatic heterocyclic group) which contains at least one (preferably 1 to 3) nitrogen atom as an atom constituting a ring system (ring atom) in addition to carbon atoms, and which may also contain 1 to 3 heteroatoms selected from oxygen and sulfur atoms.
xe2x80x9cAromatic nitrogen-containing heterocyclic groupxe2x80x9d may for example be an aromatic monocyclic nitrogen-containing heterocyclic group such as pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl (1H-imidazol-1-yl, 1H-imidazol-4-yl and the like), pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl (1,2,4-triazolyl-1-yl, 1,2,4-triazolyl-4-yl and the like), tetrazolyl, pyridyl (2-, 3- or 4-pyridyl), pyridazinyl, pyrimidinyl and pyrazinyl, triazinyl as well as an N-oxide form thereof, with a 5-to 6-membered aromatic monocyclic nitrogen-containing heterocyclic group being preferred and imidazolyl and pyridyl being particularly preferred.
A preferred pyridyl is 4-pyridyl which may have a substituent (e.g., an optionally substituted lower alkyl group) in its 2-position.
xe2x80x9cNon-aromatic nitrogen-containing heterocyclic groupxe2x80x9d may for example be a partially reduced form of xe2x80x9caromatic nitrogen-containing heterocyclic groupxe2x80x9d described above (e.g., imidazolinyl, tetrahydropyrimidinyl), as well as azetidinyl, pyrrolidinyl, piperidyl (2-, 3- or 4-piperidyl), morpholinyl, thiomorpholinyl, piperazinyl (1-piperazinyl and the like), homopiperazinyl and the like, with a 5- to 6-membered non-aromatic monocyclic nitrogen-containing heterocyclic group being preferred.
A substituent on xe2x80x9cnitrogen-containing heterocyclic groupxe2x80x9d represented by Z is one similar to a substituent on xe2x80x9cheterocyclic groupxe2x80x9d represented by R described above. A nitrogen atom which is a constituent of a nitrogen-containing heterocyclic group may be oxidized. It is also possible that the substituents on xe2x80x9cnitrogen-containing heterocyclic groupxe2x80x9d represented by Z are bound to each other to form a ring (e.g., a benzene ring).
Z is preferably an optionally substituted nitrogen-containing heterocyclic group, with an optionally substituted aromatic nitrogen-containing heterocyclic group being particularly preferred.
Compound (I) is preferably 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-[1-(4-pyridyl)piperidin-4-ylamino]-2-piperazinone, 4-(6-chloronaphthalene-2-sulfonyl)-1-[1-(4-pyridyl)piperidin-4-ylamino]-2-piperazinone, 4-(6-bromonaphthalene-2-sulfonyl)-1-[1-(4-pyridyl)piperidin-4-ylamino]-2-piperazinone, 4-(7-bromo-2H-benzopyran-3-sulfonyl)-1-[1-(4-pyridyl)piperidin-4-ylamino]-2-piperazinone, 4-(6-chloronaphthalene-2-sulfonyl)-1-{methyl[1-(4-pyridyl)piperidin-4-yl]amino}-2-piperazinone, 4-(6-bromonaphthalene-2-sulfonyl)-1-{methyl[1-(4-pyridyl)piperidin-4-yl]amino}-2-piperazinone, 4-(7-bromo-2H-benzopyran-3-sulfonyl)-1-{methyl[1-(4-pyridyl)piperidin-4-yl]amino}-2-piperazinone, 4-(6-chloronaphthalene-2-sulfonyl)-1-{ethyl[1-(4-pyridyl)piperidin-4-yl]amino}-2-piperazinone, 4-(6-chloronaphthalene-2-sulfonyl)-1-{methyl[1-(2-methyl-4-pyridyl)piperidin-4-yl]amino}-2-piperazinone, {[4-(6-chloronaphthalene-2-sulfonyl)-2-oxo-1-piperazinyl][1-(2-methyl-4-pyridyl)-4-piperidinyl]amino}acetic acid, 4-(6-chloronaphthalene-2-sulfonyl)-1-{[1-(4-pyridyl)-4-piperidinyl]amino}-6-oxo-2-piperazinecarboxylic acid, 4-(6-chloronaphthalene-2-sulfonyl)-1-{methyl[1-(4-pyridyl)-4-piperidinyl]amino}-6-oxo-2-piperazinecarboxylic acid, 4-(6-chloronaphthalene-2-sulfonyl)-1-{methyl[1-(4-pyridyl)-4-piperidinyl]amino}-6-oxo-2-piperazinecarboxamide, 4-(6-chloronaphthalene-2-sulfonyl)-1-{methyl[1-(2-methyl-4-pyridyl)-4-piperidinyl]amino}-6-oxo-2-piperazinecarboxamide, 4-(6-chloronaphthalene-2-sulfonyl)-6-hydroxymethyl-1-{methyl[1-(4-pyridyl)-4-piperidinyl]amino}-2-piperazinone, 6-aminomethyl-4-(6-chloronaphthalene-2-sulfonyl)-1-{methyl[1-(4-pyridyl)-4-piperidinyl]amino}-2-piperazinone, 6-acetylaminomethyl-4-(6-chloronaphthalene-2-sulfonyl)-1-{methyl[1-(4-pyridyl)-4-piperidinyl]amino}-2-piperazinone, 4-(6-chloronaphthalene-2-sulfonyl)-1-{[1-(4-pyridyl)-4-piperidinyl]amino}-6-oxo-2-piperazineacetic acid and 4-(6-chloronaphthalene-2-sulfonyl)-1-{[1-(2-methyl-4-pyridyl)-4-piperidinyl]amino}-6-oxo-2-piperazineacetic acid as well as a salt thereof.
A prodrug for Compound (I) means a compound which is converted into Compound (I) by a reaction with an enzyme or a gastric acid under an in vivo physiological condition, i.e. a compound which undergoes an enzymatic oxidation or reduction to form Compound (I) and a compound which is hydrolyzed by a gastric acid to form Compound (I). A prodrug for Compound (I) may for example be a compound resulting from an acylation, an alkylation or a phosporylation of an amino group of Compound (I) (for example, a compound resulting from eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylation of an amino acid of Compound (I)), a compound resulting from an acylation, an alkylation, a phosphorylation and a boration of a hydroxyl group of Compound (I) (for example a compound resulting from acetylation, palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation, alanylation, dimethylaminomethylcarbonylation of a hydroxyl group of Compound (I)), or a compound resulting from an esterification or an amidation of a carboxyl group of Compound (I) (for example a compound resulting from ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxclen-4-yl)methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidation of a carboxyl group of Compound (I)) and the like. Any of these compounds can be produced from Compound (I) by a method known per se.
A prodrug for Compound (I) may also be a compound which is changed into Compound (I) under a physiological condition described in xe2x80x9cIYAKUHIN NO KAIHATSU (Pharmaceutical development)xe2x80x9d, Vol.7, Molecular design, p163-198, HIROKAWA SHOTEN, 1990.
A salt of Compound (I) may for example be a pharmaceutically acceptable salt such as an acid addition salt with acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, cinnamic acid, fumaric acid, phosphonic acid, hydrochloric acid, nitric acid, hydrobromic acid, hydroiodic acid, sulfamic acid, sulfuric acid and the like, a metal salt with sodium, potassium, magnesium, calcium and the like, an organic. salt with trimethylamine, triethylamine, pyridine, picolin, N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine and the like.
Compound (I) or a salt thereof can be produced for example by Processes A to D described below. Each compound shown in the following methods may form a salt as long as the reaction is not affected adversely, and such salt may for example be one similar to a salt of Compound (I).




Compound (II) represented by Formula RSO2Q (II) wherein Q is a leaving group and other symbols are defined as described above or a salt thereof is reacted with Compound (III) represented by Formula (III): 
wherein the symbols are defined as described above or a salt thereof to form Compound (I).
In Formula (II) shown above, Q is a leaving group. A leaving group represented by Q may for example be a halogen atom (e.g., fluorine, chlorine, bromine, iodine) or a group which forms a reactive derivative of a sulfonic acid (e.g., sulfonic anhydride, activated sulfonyl amide, (e.g., 1,2,4-triazolide, imidazolide), a quaternary amine sulfonyl form (e.g., methylpyrrolidinium salt), bissulfonyl imide (e.g., N-phenylbissulfonyl imide) and the like).
This process is performed by reacting Compound (II) or a salt thereof with Compound (III) or a salt thereof, and a salt of Compound (II) or Compound (III) may for example be an acid addition salt with an acid which forms an acid addition salt with Compound (I) described above.
This reaction is performed generally in a solvent, and a solvent by which the reaction is not affected adversely is selected appropriately. Such solvent may for example be an alcohol such as methanol, ethanol, propanol, isopropanol, butanol and tert-butanol, an ether such as dioxane, tetrahydrofuran, diethyl ether, tert-butylmethyl ether, diisopropyl ether and ethylene glycol-dimethyl ether, an ester such as ethyl formate, ethyl acetate and n-butyl acetate, a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, trichloroethylene and 1,2-dichloroethane, a hydrocarbon such as n-hexane, benzene and toluene, an amide such as formamide, N,N-dimethylformamide and N,N-dimethylacetamide, a ketone such as acetone, methylethyl ketone and methylisobutyl ketone, a nitrile such as acetonitrile and propionitrile as well as dimethylsulfoxide, sulfolane, hexamethyl phosphoramide, water and the like, which may be employed alone or in combination with each other as a solvent mixture.
This reaction may be conducted also in the presence of a base if necessary, and such base may for example be an inorganic base such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate and sodium hydrogen carbonate as well as a tertiary amine such as triethylamine, tri(n-propyl)amine, tri(n-butyl)amine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, xcex3-collidine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine and N-methylmorpholine.
The reaction employs about 1 to about 5 moles, preferably about 1 to about 3 moles of Compound (II) per mole of Compound (III).
The reaction temperature is about xe2x88x9280xc2x0 C. to about 100xc2x0 C., preferably about xe2x88x9250xc2x0 C. to about 80xc2x0 C.
The reaction time may vary depending on the type of Compound (II) or Compound (III), the type of the solvent and the reaction temperature, and is usually about 1 minutes to about 72 hours, preferably about 15 minutes to about 24 hours.
Compound (IV) represented by Formula (IV): 
wherein Q1 is a leaving group (for example, a halogen atom (e.g., fluorine, chlorine, bromine, iodine), a group which forms a free carboxylic acid, a salt thereof (inorganic or organic salt) or a reactive derivative thereof (e.g., acid halide, ester, acid azide, acid anhydride, mixed acid anhydride, active amide, active ester, active thioester) such as a hydroxyl group) and other symbols are defined as described above is reacted with Compound (V) represented by Formula (V): 
wherein the symbols are defined as described above to form Compound (I).
This process is performed by reacting Compound (V) or a salt thereof with a free acid (IV) or a salt thereof (inorganic or organic salt) or a reactive derivative thereof (for example, acid halide, ester, acid azide, acid anhydride, mixed acid anhydride, active amide, active ester, active thioester). A salt of Compound (V) may for example be an acid addition salt with an acid which forms an acid addition salt with Compound (I) described above.
An inorganic salt employed as Compound (IV) may for example be an alkaline metal salt (for example, sodium salt and potassium salt), an alkaline earth metal (for example, calcium salt), while an organic salt employed may for example be a trimethylamine salt, a triethylamine salt, tert-butyldimehtylamine salt, a dibenzylmethylamine salt, a benzyldimethylamine salt, an N,N-dimethylaniline salt, a pyridine salt and a quinoline salt. An acid halide may for example be an acid chloride and acid bromide, an ester may for example be a lower alkyl ester such as methyl and ethyl esters, a mixed acid anhydride may for example be a mono C1-4 alkyl-carbonic acid mixed anhydride (for example, a mixed acid anhydride of a free acid (IV) with monomethyl carbonic acid, monoethyl carbonic acid, monoisopropyl carbonic acid, monoisobutyl carbonic acid, mono tert-butyl carbonic acid, monobenzyl carbonic acid, mono (p-nitrobenzyl)carbonic acid and monoallyl carbonic acid), a C1-6 aliphatic carboxylic acid mixed anhydride (for example a mixed acid anhydride of a free acid (IV) with acetic acid, cyanoacetic acid, propionic. acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, trifluoroacetic acid, trichloroacetic acid and acetoacetic acid), a C7-11 aromatic carboxylic acid mixed anhydride (for example, a mixed acid anhydride of a free acid (IV) with benzoic acid, p-toluic acid and p-chlorobenzoic acid), an organic sulfonic acid mixed anhydride (for example, with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid), and an active amide may for example be an amide with a nitrogen-containing heterocyclic compound (for example, an acid amide of a free acid (IV) with pyrazole, imidazole and benzotriazole, and such nitrogen-containing heterocyclic compound may be substituted by a C1-6 alkyl (for example, methyl, ethyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl), a C1-6 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy), a halogen atom (for example, fluorine, chlorine, bromine), oxo, thioxo, a C1-6 alkylthio (for example, methylthio, ethylthio, propylthio, butylthio) and the like).
An active ester may for example be an organic phosphate (for example, an ester such as diethoxyphosphate and diphenoxyphosphate) as well as p-nitrophenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, 6-chloro-1-hydroxybenzotriazole ester, 1- hbydroxy-1H-2-pyridone ester and the like. An active thioester may for example be an ester with an aromatic heterocyclic thiol compound [such heterocyclic ring may be substituted by a C1-6 alkyl (for example, methyl, ethyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl), a C1-6 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy), a halogen atom (for example, fluorine, chlorine, bromine), a C1-6 alkylthio (for example, methylthio, ethylthio, propylthio, butylthio) and the like], such as 2-pyridylthiol ester and 2-benzothiazolylthiol ester.
This reaction is performed generally in a solvent optionally in the presence of a base or a condensing agent (for example, carbodiimides (DCC, WSC, DIC and the like), a phosphate derivative (for example, diethyl cyanophosphate, DPPA, BOP-Cl)). Such solvent and base may be those described above in Process A.
The reaction employs about 1 to about 5 moles, preferably about 1 to about 2 moles of Compound (V) per mole of Compound (IV).
The reaction temperature is about xe2x88x9250xc2x0 C. to about 150xc2x0 C., preferably about xe2x88x9220xc2x0 C. to about 100xc2x0 C.
The reaction time may vary depending on the types of Compound (IV) or Compound (V), the types of the solvent and the base and the reaction temperature, and is usually about 1 minutes to about 100 hours, preferably about 15 minutes to about 48 hours.
Compound (VI) represented by Formula (VI): 
wherein the symbols are defined as described above or a salt thereof is reacted with a compound represented by Formula (VII) :A1xe2x80x94X2xe2x80x94Z wherein A1 is Q2xe2x80x94Yxe2x80x94 or Oxe2x95x90Yxe2x80x94 and Q2 is a leaving group (e.g., a halogen atom, a group represented by Formula:R5xe2x80x94SO2xe2x80x94Oxe2x80x94 wherein R5 is a lower alkyl group which may be substituted by a halogen atom or a phenyl group which may have a substituent) and other symbols are defined as described above or a salt thereof to form Compound (I) or a salt thereof.
This process is performed by reacting Compound (VI) with Compound (VII).
In Formula (VII) shown above, a halogen atom represented by Q2 may for example be chlorine, bromine and iodine.
In the formula shown above, a lower alkyl group which may be substituted by a halogen atom represented by R5 may for example be a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl, with a C1-4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl and isobutyl being preferred. A lower alkyl group substituted by a halogen atom (for example, fluorine, chlorine, bromine and iodine) represented by R5 may for example be trichloromehtyl and trifluoromethyl.
A substituent on a phenyl group represented by R5 may for example be a lower alkyl group (similar to a lower alkyl group represented by R5 described above), a lower alkoxy group (for example, a C1-6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy and butoxy), a halogen atom (for example, fluorine, chlorine, bromine and iodine), a nitro group, a cyano group and a carboxyl group.
A reaction in this method is performed generally in a solvent, and a solvent by which the reaction is not affected adversely is selected appropriately. Such solvent may for example be an alcohol such as methanol, ethanol, propanol, isopropanol, butanol and tert-butanol, an ether such as dioxane, tetrahydrofuran, diethyl ether, tert-butylmethyl ether, diisopropyl ether and ethylene glycol-dimethyl ether, an ester such as ethyl formate, ethyl acetate and n-butyl acetate, a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, trichloroethylene and 1,2-dichloroethane, a hydrocarbon such as n-hexane, benzene and toluene, an amide such as formamide, N,N-dimethylformamide and N,N-dimethylacetamide, a nitrile such as acetonitrile and propionitrile as well as dimethylsulfoxide, sulfolane, hexamethyl phosphoramide, water and the like, which may be employed alone or in combination with each other as a solvent mixture.
This reaction may be conducted also in the presence of a base if necessary, and such base may for example be an alkaline metal hydride such as potassium hydride and sodium hydride, a metal alkoxide having 1 to 6 carbon atoms such as lithium ethoxide, lithium t-butoxide, sodium methoxide, sodium ethoxide and carboxyl t-butoxide, an inorganic base such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate and sodium hydrogen carbonate as well as a tertiary amine such as triethylamine, tri(n-propyl)amine, tri(n-butyl)amine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, xcex3-collidine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine and N-methylmorpholine.
The reaction employs about 1 to about 100 moles, preferably about 1 to about 50 moles of Compound (VII) per mole of Compound (VI).
The reaction temperature is about xe2x88x9230xc2x0 C. to about 250xc2x0 C., preferably about xe2x88x9210xc2x0 C. to about 20xc2x0 C.
The reaction time may vary depending on the types of Compound (VI) or Compound (VII), the type of the solvent and the reaction temperature, and is usually about 1 minutes to about 72 hours, preferably about 15 minutes to about 24 hours.
Alternatively, Compound (VI) or a salt thereof is reacted with Compound (VII) having an oxo group or a salt thereof to form Compound (I) whose substituent A has a double bond, which is then subjected to a reductive amination to form Compound (I) whose substituent A has a single bond or a salt thereof.
A reducing agent employed in this reductive alkylation may for example be a metal hydrogen complex such as lithium aluminum hydride, trimethoxylithium aluminum hydride, tri-t-butoxylithium aluminum hydride, sodium aluminum hydride, sodium triethoxyaluminum hydride, sodium borohydride, sodium trimethoxyborohydride, sodium cyanoborohydride, sodium triacetoxy bodohydride, lithium borohydride, lithium cyanoborohydride and lithium triethylborohydride, as well as triethylsilane. A catalytic hydrogenation employing a catalyst may also be employed. Such catalyst may for example be a palladium catalyst such as palladium black, palladium carbon, palladium-silica gel and palladium-barium sulfate, a platinum catalyst such as platinum oxide, platinum carbon and platinum black, a rhodium catalyst such as rhodium carbon and rhodium alumina, a ruthenium catalyst such as ruthenium oxide and ruthenium carbon as well as a Raney nickel, each of which is subjected to a reaction under a hydrogen atmosphere. The amount of a catalyst to be employed per mole of Compound (I) ranges from about 0.001 to about 2 moles, preferably about 0.001 to about 1 mole. While this catalytic hydrogenation is conducted generally under an atmospheric pressure, it may be conducted also under pressure if necessary. Such pressure is usually about 1 to about 150 atms, preferably about 1 to about 100 atms.
This reaction is performed generally in a solvent, and a solvent by which the reaction is not affected adversely is selected appropriately. Such solvent may for example be an alcohol such as methanol, ethanol, propanol, isopropanol, butanol and tert-butanol, an ether such as dioxane, tetrahydrofuran, diethyl ether, tert-butylmethyl ether, diisopropyl ether and ethylene glycol-dimethyl ether, an ester such as ethyl formate, ethyl acetate and n-butyl acetate, a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, trichloroethylene and 1,2-dichloroethane, a hydrocarbon such as n-hexane, benzene and toluene, an amide such as formamide, N,N-dimethylformamide and N,N-dimethylacetamide, an organic acid such as formic acid, acetic acid and trifluoroacetic acid as well as dimethylsulfoxide, sulfolane, hexamethyl phosphoramide, water and the like, which may be employed alone or in combination with each other as a solvent mixture.
This reaction may be conducted also in the presence of an acid if necessary, and such acid may for example be a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and perchloric acid, a sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and camphorsulfonic acid, an organic acid such as formic acid, acetic acid, propionic acid and trifluoroacetic acid. The amount of such acid to be employed per mole of Compound (I) ranges from about 0.01 to about 20 moles, preferably about 0.1 to about 10 moles.
The reaction temperature is about xe2x88x9230xc2x0 C. to about 150xc2x0 C., preferably about xe2x88x9210xc2x0 C. to about 120xc2x0 C.
The reaction time may vary depending on the type of Compound (I), the type of the solvent and the reaction temperature, and is usually about 10 minutes to about 72 hours, preferably about 15 minutes to about 48 hours.
Among the compounds represented by Formula (VI), a compound whose R3 is an acyl group is a novel compound, and useful as an intermediate for synthesizing a compound represented by Formula (I) or a salt thereof.
Compound (VIII) represented by Formula (VIII): 
wherein Q3 is a leaving group (for example a hydrogen atom when being bound to a nitrogen atom in Y or X2, a halogen atom, a moiety capable of cross-coupling (for example, a substituent and being bound via boron, tin, magnesium and the like), a group represented by Formula:R6xe2x80x94SO2xe2x80x94O wherein R6 is a lower alkyl group which may be substituted by a halogen atom or a phenyl group which may have a substituent when being bound to a carbon atom in Y or X2) and other symbols are defined as described above or a salt thereof is reacted with Compound (IX) represented by Formula Zxe2x80x94Q4 (IX) wherein Q4 is a leaving group (a halogen atom, a group represented by Formula R7xe2x80x94SO2xe2x80x94Oxe2x80x94 wherein R7 is a lower alkyl group which may be substituted by a halogen atom or a phenyl group which may have a substituent, a moiety capable of cross-coupling and being bound via boron, tin, magnesium and the like) when Z is not an optionally substituted amino group, or Q4 is a hydrogen atom when Z is an optionally substituted amino group and other symbols are defined as described above or a salt thereof to form Compound (I).
In the formula shown above, a halogen atom represented by Q3 may for example be chlorine, bromine and iodine. Each of R6 and R7 s a lower alkyl group which may be substituted by a halogen atom or a phenyl group which may have a substituent. A lower alkyl group represented by R6 and R7 may for example be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl and hexyl, with methyl, ethyl, propyl, isopropyl and butyl being preferred. A halogen atom may for example be fluorine, chlorine, bromine and iodine, which may occur 1 to 9 times, preferably 1 to 5 times in any substitutable positions. A substituent on a phenyl group which may have a substituent may for example be a lower alkyl group (for example a C1-6 alkyl group such as methyl, ethyl, propyl and butyl), a lower alkoxy group (e.g., A C1-6 alkoxy group such as methoxy, ethoxy, propoxy and butoxy), a halogen atom (e.g., fluorine, chlorine, bromine and iodine), a nitro group, a cyano group and a carboxyl group.
This process optionally employs a metal catalyst to promote a reaction. Such metal catalyst may for example be a palladium compound [e.g., palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium chloride, dichlorobis(triethylphosphine)palladium, tris(dibenzylideneacetone)dipalladium-2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl], a nickel compound [e.g., tetrakis(triphenylphosphine)nickel, bis(triethylphosphine)nickel chloride, bis(triphenylphosphine)nickel chloride], a rhodium compound [e.g., tri(triphenylphosphine)rhodium chloride], with a palladium compound being preferred. The amount of such catalyst per mole of Compound (VIII) ranges from about 1 to 0.000001 moles, preferably about 0.1 to 0.00001 moles.
This reaction may be performed also in a sealed tube.
Compound (I) whose Z is an optionally substituted amidino group can be produced by reacting Compound (VIII) whose Q3 is a cyano group or a salt thereof with a lower alcohol to form an iminoether and then reacting with an amine.
A lower alcohol may for example be a C1-4 alcohol such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol and 2-butanol.
This reaction is performed usually in a solvent. Such solvent may be one exemplified in Process A, and an alocohol itself may serve also as a solvent.
This reaction is performed usually in the presence of acid (e.g., an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, an organic acid such as methanesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, acetic acid and trifluoroacetic acid) and a base (e.g., potassium methoxide, sodium methoxide, sodium ethoxide, potassium t-butoxide). Each of these acids and bases may be used in an amount ranging from a catalytic amount (about 0.001 moles) to a large excess.
The reaction temperature is about xe2x88x9250xc2x0 C. to about 150xc2x0 C., preferably about xe2x88x9220xc2x0 C. to about 100xc2x0 C.
The reaction time may vary depending on the type of Compound (III) and the types of the acid, the base and the solvent, and is usually about 30 minutes to about 240 hours, preferably about 1 hour to about 120 hours.
An iminoether is reacted with an amine (e.g., ammonia; a primary amine such as methylamine, ethylamine and propylamine; a secondary amine such as dimethylamine, diethylamine, methylethylamine, di-n-propylamine, pyrrolidine, piperidine, morpholine, piperazine and 1-methylpiperazine; an aromatic amine such as aniline and N-methylaniline) to form Compound (I).
While this reaction is performed usually in a solvent and such solvent may be any solvent as long as the reaction is not affected adversely, a solvent exemplified in Process A is employed preferably. Alternatively, an amine itself may serve also as a solvent.
The reaction temperature is about xe2x88x9220xc2x0 C. to about 200xc2x0 C., preferably about xe2x88x9210xc2x0 C. to about 150xc2x0 C.
The reaction time may vary depending on the types of the iminoether, the amine and the solvent, and is usually about 30 minutes to about 240 hours, preferably about 1 hour to about 120 hours. This reaction may be performed also in a sealed tube.
Any of starting Compounds (III), (IV), (VI) and (VIII) employed in Processes A to D described above can be produced by a method known per se or an analogous method. 
Compound (X) represented by Formula (X): 
wherein L1 is a protecting group for an amino group, and other symbols are defined as described above or a salt thereof is reacted with Compound (V) represented by Formula (V): 
wherein each symbol is defined as described above or a salt thereof to form Compound (XIII) represented by Formula (XIII): 
wherein each symbol is defined as described above.
In Formulae (X) and (XIII), a protective group represented by L1 may for example be a formyl group, a C1-6 alkyl-carbonyl group (for example, acetyl, ethylcarbonyl), a C1-6 alkyl-sulfonyl group, a tert-butyloxycarbonyl group, a benzyloxycarbonyl group, an allyloxycarbonyl group, a fluorenylmethyloxycarbonyl group, an arylcarbonyl group (for example, phenylcarbonyl, naphthylcarbonyl), an arylsulfonyl group (for example, phenrylsulfonyl, naphthylsulfonyl), a C1-6 alkyloxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl), a C7-10 aralkyl-carbonyl group (for example, benzylcarbonyl), a methyl group, an aralkyl group (for example, benzyl, diphenylmethyl, trimethyl group) and the like. Each of these groups may be substituted by 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine), nitro groups and the like.
This reaction employs the reactive derivative, the reaction condition, the reaction solvent and the reaction time which are similar or analogous to those in the reaction between Compound (IV) and Compound (V) in Process B described above.
Compound (XII) represented by Formula (XII): 
wherein L1 is a protecting group for an amino group, and other symbols are defined as described above or a salt thereof is reacted with Compound (VII) represented by Formula (VII):
Axe2x80x94X2xe2x80x94Zxe2x80x83xe2x80x83(VII)
wherein each symbol is defined as described above or a salt thereof to form Compound (XIII) represented by Formula (XIII): 
wherein each symbol is defined as described above.
This reaction employs the reactive derivative, the reaction condition, the reaction solvent and the reaction time which are similar or analogous to those in the reaction between Compound (VI) and Compound (VII) in Process C described above.
Compound (X) represented by Formula (X): 
wherein each symbol is defined as described above or a salt thereof is reacted with a hydrazine derivative represented by Formula: 
wherein L2 is a protecting group for an amino group, and other symbols are defined as described above or a salt thereof and then the protecting group of the amino group in the hydrazine is deprotected selectively to form Compound (XII) represented by Formula (XII): 
wherein each symbol is defined as described above or a salt thereof.
This reaction employs the reactive derivative, the reaction condition, the reaction solvent and the reaction time which are similar or analogous to those in the reaction between Compound (IV) and Compound (V) in Process B described above.
In order to deprotect the protective group of an amino group in the hydrazine, a method per se or a method analogous thereto is employed, for example by using an acid, a base, a reduction, an ultraviolet, palladium acetate and the like.
Compound (VII) represented by Formula (VII):
Axe2x80x94X2xe2x80x94Zxe2x80x83xe2x80x83(VII)
wherein each symbol is defined as described above or a salt thereof is reacted with a hydrazine derivative represented by Formula: 
wherein L3 is a protecting group for an amino group, and other symbols are defined as described above or a salt thereof and then the protecting group of the amino group is deprotected to form Compound (V) represented by Formula (V): 
wherein each symbol is defined as described above or a salt thereof.
This reaction employs the reactive derivative, the reaction condition, the reaction solvent and the reaction time which are similar or analogous to those in the reaction between Compound (VI) and Compound (VII) in Process C described above.
In order to deprotect the protective group of an amino group, a method per se or a method analogous thereto is employed, for example by using an acid, a base, a reduction, an ultraviolet, palladium acetate and the like.
An amide nitrogen atom in Compound (XI) represented by Formula (XI): 
wherein each symbol is defined as described above is aminated to produce Compound (XII) represented by Formula (XII): 
wherein each symbol is defined as described above or a salt thereof.
An aminating agent employed preferably in this amination may for example be an O-acylhydroxylamine such as O-diphenylphosphinyl hydroxylamine, hydroxylamine O-sulfate, O-(2,4,6-trimethylbenzenesulfonyl)hydroxylamine and the like.
This reaction is conducted usually in the presence of a base. Preferable base may for example be an alkaline metal hydride such as sodium hydride and potassium hydride, an alkaline metal hydroxide such as lithium hydroxide, sodium hydroxide and potassium hydroxide, an alkaline earth metal hydroxide such as magnesium hydroxide and calcium hydroxide, an alkaline metal carbonate such as sodium carbonate and potassium carbonate, an inorganic base of an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, an alkaline metal alcholate such as sodium methylate, sodium ethylate, potassium methylate and tert-butoxypotassium, an organic base such as trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane and 1,8-diazabicyclo[5.4.0]-7-undecene, a lithium salt such as methyllithium, n-butyllithium, sec-butyllithium and tert-butyllithium as well as a lithium amide such as lithium diisopropylamide.
This reaction is conducted generally in a solvent. Such solvent may be one exemplified in Process A described above.
While the reaction employs a base in an amount of about 1 to 10 moles, preferably about 1 to about 20 moles per mole of Compound (XI), the base itself may sometimes serve as a solvent.
The reaction temperature is about xe2x88x92100xc2x0 C. to about 200xc2x0 C., preferably about xe2x88x9278xc2x0 C. to about 100xc2x0 C.
The reaction time may vary depending on the types of Compound (XI), the aminating agent, the base and the solvent as well as the reaction temperature, and is usually about 1 hour to about 200 hours, preferably about 5 minutes to about 100 hours.
An amino protecting group in Compound (XIII) represented by Formula (XI): 
wherein each symbol is defined as described above or a salt thereof is deprotected to produce Compound (III) represented by Formula (III): 
wherein each symbol is defined as described above or a salt thereof.
In order to deprotect the protective group of an amino group, a method per se or a method analogous thereto is employed, for example by using an acid, a base, a reduction, an ultraviolet, palladium acetate and the like.
Compound (XIX) and Compound (XV) represented by Formula (XIV): 
or Formula (XV): 
wherein each symbol is defined as described above or a salt thereof is sulfonylated by a compound represented by Formula Rxe2x80x94SO2Q wherein each symbol is defined as described above to form Compound (IV) and Compound (VI) represented by Formula (IV): 
or Formula (VI): 
wherein each symbol is defined as described above or a salt thereof, respectively.
Compound (VIII) represented by Formula (VIII): 
wherein each symbol is defined as described above or a salt thereof can be produced using Compound (II) with Compound (XVI), Compound (IV) with Compound (XVII) and Compound (VI) with Compound (XVIII) by the procedures described in Processes A, B and C, respectively. 
In Process G described above, a compound obtained before a deprotection step, which is represented by Formula: 
wherein each of L1 and L2 is a protecting group for an amino group and other symbols are defined as described above or a salt thereof and a compound obtained by subjecting it to an appropriate deprotection step or a salt thereof is encompassed by a compound represented by Formula: 
wherein each of L1a and L2a is a hydrogen atom or a protecting group for an amino group and other symbols are defined as described above or a salt thereof, among which a compound represented by Formula: 
wherein each of L1a and L2a is a hydrogen atom or a protecting group for an amino group and R1xe2x80x2 and R2xe2x80x2 are bound to each other to form an optionally substituted ring, or, R1xe2x80x2 is an hydrogen atom or an optionally substituted hydrocarbon group and a substituent on X1 and R2xe2x80x2 are bound to each other to form an optionally substituted ring and other symbols are defined as described above or a salt thereof is a novel compound and useful as an intermediate for synthesizing a compound represented by Formula (I) or a salt thereof.
In the formula shown above, a protecting group for an amino group represented by L1a and L2a may for example be similar to a protecting group for an amino group represented by L1, and may also be xe2x80x9csulfonic acid-derived acyl groupxe2x80x9d or xe2x80x9ccarboxylic acid-derived acyl groupxe2x80x9d as a substituent on xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d and xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R. It is preferable that one of L1a and L2a is not a hydrogen, and it is more preferable that L1a is a protecting group for an amino group while L2a is a hydrogen atom.
Such intermediate is preferably a compound in which R1xe2x80x2 and R2xe2x80x2 are bound to each other and taken together with xe2x80x94Nxe2x80x94X1xe2x80x94CDxe2x80x94Nxe2x80x94 to form a group represented by Formula: 
wherein X3 is an optionally substituted C1-2 alkylene, X4 is an optionally substituted C1-3 alkylene and D is an oxygen atom or a sulfur atom, more preferably a compound in which R1xe2x80x2 and R2xe2x80x2 are bound to each other and taken together with xe2x80x94Nxe2x80x94X1xe2x80x94CDxe2x80x94Nxe2x80x94 to form a group represented by Formula: 
wherein n is 1 or 2, mxe2x80x3 is 1 or 2, R8 is a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted mercapto group, a nitro group, a cyano group, an optionally substituted amino group, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group or an optionally substituted sulfamoyl group (preferably, a hydrogen atom, an optionally substituted lower alkyl group, a cyano group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group or an optionally substituted thiocarbamoyl group), and D is an oxygen atom or a sulfur atom, and particularly a compound in which R1xe2x80x2 and R2xe2x80x2 are bound to each other and taken together with xe2x80x94Nxe2x80x94X1xe2x80x94CDxe2x80x94Nxe2x80x94 to form a group represented by Formula: 
wherein n is 1 or 2 and m is 2 or 3 (more preferably n=1 and m=2).
Such synthetic intermediate may also be a compound in which a substituent on X1 and R2 are bound to each other and a divalent group represented by xe2x80x94X1xe2x80x94CDxe2x80x94N(R2)xe2x80x94 is a group represented by Formula: 
wherein X5 is a bond or an optionally substituted methylene, X6 is an optionally substituted C2-3 alkylene and D is an oxygen atom or a sulfur atom, more preferably a compound in which a substituent on X1 and R2 are bound to each other and a divalent group represented by xe2x80x94X1xe2x80x94CDxe2x80x94N(R2)xe2x80x94 is a group represented by Formula: 
wherein nxe2x80x2 is 0 or 1 and mxe2x80x2 is 2 or 3 (more preferably nxe2x80x2=0 and mxe2x80x2=2).
Any of starting Compounds (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIV) (XV), (XVI), (XVII) and (XVIII) employed in Processes A to L described above can be produced by a method known per se or an analogous method.
When a compound obtained by each reaction according to the invention is in a free form, then it can be converted into a salt in accordance with a standard method, and when it is obtained in the form of a salt, then it can be converted into a free form or other salts.
Compound (I) thus obtained can be isolated and purified from a reaction mixture by a method known per se such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin layer chromatography and the like.
A salt of Compound (I) can be produced by adding an inorganic or organic acid to Compound (I) by a method known per se.
When Compound (I) can exist as a stereoisomer, any of such individual isomers and mixtures thereof are encompassed in the scope of the invention, and any of such isomers can exclusively be produced if necessary.
It is also possible that Compound (I) or a salt thereof is a hydrate, and both of a hydrate and an anhydride are included in the invention.
A compound comprising as its moiety a divalent group represented by Formula: 
wherein R1xe2x80x2 and R2xe2x80x2 are bound to each other to form an optionally substituted ring, or R1xe2x80x2 is a hydrogen atom or an optionally substituted hydrocarbon group and a substituent of X1 and R2xe2x80x2 are bound to each other to form an optionally substituted ring, and other symbols are defined as described above or a salt thereof (including Compound (I); preferably a compound comprising as its moiety a divalent group represented by Formula: 
wherein B is an optionally substituted piperazinone ring and R3 is defined as described above or a salt thereof, a compound comprising as its moiety a divalent group represented by Formula: 
wherein Ring E is an optionally substituted pyrrolidone ring and R3 is defined as described above or a salt thereof, and the like) has an effect mimicking any of various peptides (including proteins) (especially an effect mimicking a peptide at the site on which said peptide exerts its physiological effect), and accordingly it is useful as an enzyme inhibitor, a receptor regulator (e.g., receptor antagonist, receptor agonist), an ion channel regulator (e.g., ion channel blocker, ion channel opener) and the like. Thus, it is possible to inhibit the formation of an enzyme-substrate complex by means of mimicking an enzyme""s catalytic site and/or a substrate""s binding site, and a use as an agonist or antagonist of a receptor is also possible by means of mimicking a receptor""s ligand.
Such enzyme inhibitors may for example be activated coagulation factor inhibitors such as activated coagulation factor X inhibitors, thrombin inhibitors and activated coagulation factor VII inhibitors, plasmin inhibitors, kallikrein inhibitors, nitrogen monooxide synthetase inhibitors, HIV reverse transcriptase inhibitors, HIV protease inhibitors, farnesyl protein transferase inhibitors, various matrix metalloprdtease inhibitors, tyrosine phosphatase inhibitors, cyclin-dependent kinase inhibitors, protein tyrosine kinase inhibitors, various protein kinase inhibitors, telomerase inhibitors, cathepsin inhibitors, elastase inhibitors, phosphodiesterase inhibitors, various serine protease inhibitors, interleukin-1xcex2 converting enzyme inhibitors, various cysteine protease inhibitors and the like, while receptor regulators may for example be antagonists and agonists of receptors including-fibrinogen receptors such as glycoprotein (GP) IIb/IIIa, integrins (vitronectin receptors), thrombin receptors, orphan receptors, intranuclear receptors, adrenaline receptors, histamine receptors, angiotensin II receptors, endoserine receptors, leukotriene receptors, thromboxanthine receptors, chemokine receptors, opioid receptors, adenosin receptors, tachykinin receptors such as substance P or neurokinins, bradykinin receptors, prostaglandin receptors, dopamine receptors, serotonin receptors, adrenocorticotropic hormone releasing factor (CRF) receptors, LH-RH receptors, somatostatin receptors, glucagon receptors, various G protein-conjugated receptors, insulin-like growth factor receptors (IGF), and receptors of various growth factors such as epithelial growth factors (EGF), fibrocyte growth factors (FGF), platelet-derived growth factors (PDGF), hepatocyte growth factors (HGF), vascular endothelium growth factors (VEGF), transformation growth factors (TGF), nerve growth factors (NGF) and tumor necrosis factors (TNF), erythropoietin (EPO), thrombopoietin (TPO), receptors of various stimulating factors such as granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF) and macrophage colony stimulating factor (M-CSF), receptors of various cytokines such as interleukin-1, interleukin-6 and interleukin-8 as well as hormone receptors, and ion channel regulators may for example be antagonists and agonists of ion channels for calcium, potassium and chlorine.
Each of Intermediates (XIX) and (XXVIII) which is useful especially as a backbone mimicking a peptide in designing the molecules of such enzyme inhibitors, receptor regulators (e.g., receptor antagonists, receptor agonists) and ion channel regulators (e.g., ion channel blockers and ion channel openers) can be synthesized for example by the methods described in Sections [1] to [6] or the methods described in Sections [7] to [9] described below. 
wherein each symbols is defined as described above. Methods for producing Compound (XIX)
[1] Process M: A synthesis can be effected by subjecting a hydrazine compound (XX) to an intramolecular acylation. Usually, a solvent which is not involved in the reaction is employed, and a condensation with a carboxylic acid is effected preferably in the presence of a condensing agent. It is also possible to perform a reaction in the presence of a base or acid catalyst.
[2] Process N: A synthesis can be effected by means of a ring closure reaction of an acid hydrazide compound (XXI). When Q4 is a leaving group, the reaction is performed preferably in the presence of a base. It is also possible that Q4 is a hydroxyl group, and in such case a synthesis can be effected by Mitsunobu reaction. When Q4 together with R8 forms a conjugated double bond, a synthesis can readily be effected by performing a conjugate addition reaction in the presence of a base catalyst.
[3] Process O: A synthesis can be effected by performing a ring closure reaction in the presence of a base.
[4] Process P: A synthesis can be effected by performing a reaction of an amino acid hydrazide compound (XXIII) in the presence of a base with 1,2-dibromaethane (instead of the bromo moiety, a leaving group such as iodo or trifluoromethanesulfonyloxy may be present.).
[5] Process Q: A synthesis can be effected by subjecting a piperazinone compound (XXIV) to an amination reaction for example in the presence of a base such as sodium hydride using an aminating agent such as O-diphenylphosphinyl hydroxylamine.
[6] Process R: Compound (XXVII) can be synthesized by subjecting a carbonyl compound (XXV) or (XXVI) or an acetal-protected form to a ring closure reaction in the presence of an acid catalyst. Subsequently, Compound (XXVII) is hydrogenated in accordance with Process S, whereby synthesizing Compound (XIX). Methods for producing Compound (XXVIII)
[7] Process M: A synthesis can be effected by subjecting a hydrazine compound (XXIX) to an intramolecular acylation. Usually, a solvent which is not involved in the reaction is employed, and a condensation with a carboxylic acid is effected preferably in the presence of a condensing agent. It is also possible to perform a reaction in the presence of a base or acid catalyst.
[8] Process N: A synthesis can be effected by means of a ring closure reaction of an acid hydrazide compound (XXX). When Q4 is a leaving group (for example, dimethylsulfonium group, bromine, iodine, various sulfonyloy group), the reaction is performed preferably in the presence of a base. It is also possible that Q4 is a hydroxyl group, and in such case a synthesis can be effected by Mitsunobu reaction.
[5] Process Q: A synthesis can be effected by subjecting a pyrrolidinone compound (XXXI) to an amination reaction for example in the presence of a base such as sodium hydride using an aminating agent such as O-diphenylphosphinyl hydroxylamine.
Since Compound (I) according to the invention or a salt thereof has a low toxicity and is safe and it inhibits an FXa and has an anticoagulative effect, it is useful in preventing or treating a disease such as those listed below in animals especially in mammals (for example, human, monkey, cat, pig, horse, cattle, mouse, rat, guinea pig, dog, rabbit), and is preferred especially when being used in preventing or treating an atrial fibrillation-induced cerebral infarction and deep vein thrombosis.
Brain:
Atrial fibrillation-induced cerebral infarction, acute ischemic apoplexy, acute cerebral thrombosis, cerebrovascular spasm after subarachnoid hemorrhage, Alzheimer""s disease, transient cerebral ischemic attack (TIA), mixed dementia, cerebrovascular/multi-infarct dementia
Heart:
Acute cardiac infarction, sequela of myocardial infarction, unstable angina, angina pectris, vascular reocclusion and restenosis after coronary intervention such as stenting, PTCA (percutaneous transluminal coronary angioplasty) and atherectomy Peripheral organs: Deep vein thrombosis, peripheral blood disease, adult respiratory distress syndrome, chronic renal disease (for example, diabetic nephrosis, chronic glomerulonephritis, IgA nephrosis), diabetic circulatory disorder, pain, neuropathy
Others:
Dialysis-induced thrombocytopenia, thrombocytopenia after major surgery, arterial sclerosis, cancer metastasis, systemic inflammatory response syndrome (SIRS) or pancreatitis- or cancer-related disseminated intravascular coagulation (DIC), implant rejection, implant organ protection or improvement, shock- or DIC-related various organ failures (for example, pulmonary insufficiency, hepatic insufficiency, renal insufficiency, cardiac insufficiency)
Compound (I) of the invention or a salt thereof can orally or parenterally be administered as it is or in combination with a pharmaceutically acceptable carrier.
A formulation containing Compound (I) or a salt thereof can be given orally in a dosage form such as tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (including soft capsules), syrups, emulsions and suspensions, while it can be given parenterally in a dosage form such as injection, infusion and dripping formulations as well as suppositories.
While the amount of Compound (I) or a salt thereof in a formulation of the invention may vary depending on the form of the formulation, it is usually 2 to 85% by weight, preferably 5 to 70% by weight based on the entire amount of the formulation.
A method for formulating Compound (I) or a salt thereof into a dosage form described above, a known method employed generally in the art can be applied. Also for producing a dosage form described above, appropriate amounts of appropriate additives employed usually in the pharmaceutical field such as excipients, binders, disintegrants, lubricants, sweeteners, surfactants, suspending agents, emulsifiers and the like can be incorporated.
For example, Compound (I) or a salt can be formulated into a tablet by incorporating an excipient, a binder, a disintegrant, a lubricant and the like, while it can be formulated into a pill or a granule by incorporating an excipient, a binder, a disintegrant and the like. It can be formulated also into a powder or a capsule by incorporating an excipient, into a syrup by incorporating a sweetener, into an emulsion or a suspension by incorporating a suspending agent, a surfactant, an emulsifier and the like.
An excipient may for example be lactose, sugar, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium hydrogen carbonate, calcium phosphate, calcium sulfate and the like.
A binder may for example be 5 to 10% by weight starch glue, 10 to 20% by weight gum arabic or gelatin, 1 to 5% by weight tragacanth gum, carboxymethyl cellulose, sodium alginate, glycerin and the like.
A disintegrant may for example be a starch, calcium carbonate and the like.
A lubricant may for example be magnesium stearate, stearic acid, calcium stearate, purified talc and the like.
A sweetener may for example be glucose, fructose, inverted sugar, sorbitol, xylitol, glycerin, syrups simplex and the like.
A surfactant may for example be sodium laurylsulfate, polysorbate 80, sorbitan monofatty ester, polyoxyl stearate 40 and the like.
A suspending agent may for example be gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, bentonite and the like.
An emulsified may for example be gum arabic, tragacanth gum, gelatin, polysorbate 80 and the like.
Also for formulating Compound (I) or a salt thereof into a dosage form described above, appropriate amounts of appropriate additives employed usually in the pharmaceutical field such as colorants, preservatives, flavors, seasonings, stabilizers, thickening agents and the like can be incorporated if necessary.
A formulation according to the invention containing Compound (I) or a salt thereof is stable and has a low toxicity, and can be used safely. Its daily dose may vary depending on the condition and the body weight of the patient, the type of the compound and the administration route, and is usually about 1 to 1000 mg as an active ingredient (Compound (I) or a salt thereof) per day in an adult weighing about 60 kg when given orally to a patient having a thrombosis, preferably about 3 to 300 mg, more preferably about 10 to 200 mg, which can be given at once, or divided into two or 3 dosages.
When Compound (I) of the invention or a salt thereof is given parenterally, it is given usually in a liquid formulation (for example, injection formulation). In such case, a single dosage may vary depending on the target organ, the condition and the administration mode, and is usually about 0.01 mg to about 100 mg per kg body weight when given in an injection formulation, preferably about 0.01 to about 50 mg, more preferably about 0.01 to about 20 mg, which is given conveniently via an intravenous injection. In addition to the intravenous injection formulation, a subcutaneous injection formulation, an intradermal injection formulation, an intramuscular injection formulation and a dripping injection formulation may also included in the injection formulation, and an iontophoresis percutaneous formulation is included in a sustained release formulation. Any of such injection formulations can be prepared by a method known per se, i.e., by dissolving, suspending or emulsifying Compound (I) of the invention or a salt thereof in an aseptic aqueous or oily liquid. An aqueous liquid for an injection may for example be a physiological saline and an isotonic solution containing glucose or other auxiliary agents (for example, D-sorbitol, D-mannitol, sodium chloride and the like), which may be used in combination with a suitable solubilizing aid such as an alcohol (for example, ethanol), a polyalcohol (for example, propylene glycol, polyethylene glycol), a nonionic surfactant (for example, polysorbate 80, HCO-50) and the like. An oily liquid may for example be a sesame oil and a soybean oil, which may be used in combination with a solubilizing aid such as benzyl benzoate and benzyl alcohol. Those which may also be incorporated are a buffering agent (for example, phosphate buffer and sodium acetate buffer), an analgesic (for example, benzalkonium chloride and procaine hydrochloride), a stabilizer (for example, human serum albumin and polyethylene glycol), a preservative (for example, benzyl alcohol and phenol) and the like. An injection formulation thus prepared is contained usually in an ampule.
A formulation of the invention may appropriately be used in combination with a thrombolytic agent (for example, TPA, heparin and urokinase), an Alzheimer treating agent (for example, Avan and Calan), a cholesterol treating agent (for example, HMG-CoA reductase inhibitor such as simvastatin and pravastatin), a TG reducing agent (for example, clofibrate), an AII antagonist (for example, blopress), an antiplatelet agent (for example, aspirin), a Ca antagonist (for example, calslot and amlodipine) and the like, and an appropriate amount of any of these agents may be incorporated.
The present invention is further detailed in the following Reference Examples, Examples, Formulation Examples and Experiments, which serve only as examples and are not intended to restrict the invention and can be modified without departing the scope of the invention.
An elution of a column chromatography in Reference Examples and Examples was conducted with observing by a TLC (thin layer chromatography). In the observation of a TLC, a TLC plate employed was a 60F254 manufactured by Merck and a development was performed using a solvent which was employed as an eluent in a column chromatography, while an UV detector was used for a detection. The silica gel packed in the column was kiesel gel 60 (70 to 230 mesh) manufactured by Merck. An NMR spectrum was determined by a spectrometer model Varian Gemini 200 using tetramethylsilane as an internal or external standard and the data were represented as total xcex4 values in ppm. An IR spectrum was determined by a Shimadzu spectrometer model FTZR-8200. A figure in a bracket indicated in conjunction with a mixed solvent is a volume ratio of the constituent solvents. A % value indicated in conjunction with a solution is an amount in gram contained in 100 ml of the solution. The following abbreviations are employed in Reference Examples and Examples.
s: singlet
d: doublet
t: triplet
q: quartet
dd: double doublet
m: multiplet
br: broad
brs: broad singlet
J: coupling constant
WSC: water-soluble carbodiimide
THF: tetrahydrofuran
DMF: dimethylformamide
DMSO: dimethylsulfoxide
HOBt: 1-hydroxybenzotriazole